Imaging of Central Nervous System Disorders of Protein Folding

Neurodegenerative disorders have traditionally been classified according to clinical syndromes or patterns of anatomical involvement on neuroimaging. However, growing evidence demonstrates that similar clinical phenotypes may arise from distinct molecular pathologies, while a single pathogenic protein may manifest with diverse clinical and imaging presentations. This has led to the emergence of the proteinopathy paradigm, which conceptualizes neurodegeneration as a disorder of protein misfolding, aggregation, and consequent pathologic changes. This review provides an imaging-focused overview of the major central nervous system proteinopathies, including prion diseases, amyloid-β-related disorders, tauopathies, synucleinopathies, and TAR DNA-binding protein 43-associated diseases. We discuss the presence of distinct and often predictable radiological phenotypes in these conditions, which can help in diagnosis, predict clinical progression, and explain clinical phenotype. Conventional magnetic resonance imaging remains central to structural pattern recognition, while advanced techniques such as diffusion-weighted imaging, susceptibility-weighted imaging, perfusion imaging, and quantitative volumetry may enhance diagnostic confidence. Molecular imaging with fluorodeoxyglucose positron emission tomography and emerging amyloid and tau tracers further enables in vivo characterization of disease-specific metabolic and molecular signatures. By integrating molecular mechanisms with imaging findings, this review highlights the role of neuroimaging as a bridge between microscopic protein pathology and macroscopic disease expression. Understanding proteinopathy-specific imaging patterns allows a shift from symptom-led diagnosis toward a biology-driven framework, improving diagnostic accuracy, prognostication, and the potential for targeted therapeutic monitoring in neurodegenerative disease.