Imaging of Proteinopathies in the Brains of Parkinsonian Disorders.

Abstract

Neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD), and α-synucleinopathies-including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)-are characterized by the accumulation of misfolded protein aggregates. Advances in positron emission tomography (PET) imaging have enabled in vivo visualization of these pathologies, particularly tau and α-synuclein fibrils, facilitating early diagnosis and differential classification. Tau PET tracers such as ¹⁸F-florzolotau have demonstrated robust imaging of both AD-type and 4-repeat tauopathies, including atypical parkinsonian syndromes in FTLD such as progressive supranuclear palsy and corticobasal degeneration. Cryo-electron microscopy has elucidated the molecular interactions underlying tracer binding, highlighting hydrophobic grooves in cross-βstructures as binding components commonly present in multiple tau fibril types. For α-synucleinopathies, new tracers with a modified cross-β-binding scaffold, including ¹⁸F-SPAL-T-06 and ¹⁸F-C05-05, have shown promise in detecting MSA-related pathology and, more recently, midbrain pathology in PD and DLB. However, sensitive detection of pathologies in early PD/DLB stages remains a challenge. The integration of high-resolution PET technologies and structurally optimized ligands may enable earlier and more accurate detection of protein aggregates, supporting both clinical decision-making and the development of targeted disease-modifying therapies.