Objective: To investigate disease-specific spatiotemporal progression in Progressive supranuclear palsy (PSP) patients using 18F-fluorodeoxyglucose (FDG) PET and the Subtype and Stage Inference (SuStaIn) algorithm, to explore clinically progressive subtypes and provide a comprehensive understanding of disease mechanisms.

Background: PSP is a neurodegenerative disorder that is characterized by tau pathology and diverse clinical presentations and progression patterns. Sequential tau distribution in different brain regions has been modelled, and a six-part staging system with caudal or rostral predominance has been proposed to further identify clinical subtypes. It has been reported that FDG-PET, which assesses regional cerebral glucose metabolism as a marker of neuronal function, may have better clinical relevance. FDG-PET is therefore a potential tool for exploring clinical progression and validating neuropathological staging in PSP.

Method: The present study involved 72 PSP patients and 70 healthy controls. Patients underwent a battery of neuropsychological assessments and dual PET imaging (FDG and dopamine transporter). The SuStaIn algorithm was then applied to FDG-PET data to identify the distinct disease progression subtypes.

Results: Two PSP progression subtypes were identified: the cortical subtype, marked by early prefrontal lobe hypometabolism, and the brainstem subtype, with initial midbrain changes. Cortical subtype patients showed more reduced dopamine transporter uptake in the accumbens, caudate, and anterior putamen, alongside greater cognitive decline and disease severity than those with the brainstem subtype, despite similar disease durations. Both subtypes appeared in common clinical phenotypes, PSP-Richardson’s syndrome and PSP-parkinsonism, predominantly cortical, while the PSP-progressive gait freezing phenotype was mainly associated with the brainstem subtype.

Conclusion: A combination of FDG-PET and the SuStaIn algorithm effectively identified two distinct spatiotemporal progression subtypes in PSP, termed cortical and brainstem subtype. Frontostriatal circuit disruption likely plays an important role in PSP pathophysiology, particularly in patients with the cortical subtype. From the perspective of neuronal function, our findings complement the hypothesis of distinct subtypes based on pathological progression. Concomitant PSP-cortical phenotypes and early cognitive impairment should be considered in future clinical studies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/metabolic-progressive-subtypes-in-progressive-supranuclear-palsy/