# Early subtypes and progressions of progressive supranuclear palsy: a data-driven brain bank study

## TL;DR

This study identifies seven early subtypes of progressive supranuclear palsy and their progression patterns using a data-driven approach, aiding clinical understanding and trial recruitment.

## Contribution

A novel aggressive PSP subtype (PSP-PF) and a decision tree model for early subtyping are introduced.

## Key findings

- PSP-PF shows rapid progression, short disease duration, and high tau burden.
- PSP-F and PSP-P have longer disease durations, with frontal symptoms appearing years before others.
- PSP-CBS was not identified as an independent subtype in this dataset.

## Abstract

Progressive supranuclear palsy (PSP) is typically characterized by vertical supranuclear gaze palsy and early falls, referred to as Richardson’s syndrome (PSP-RS). Other presentations include postural instability (PSP-PI), Parkinsonism (PSP-P), speech/language disorder (PSP-SL), frontal presentation (PSP-F), ocular motor dysfunction (PSP-OM), and corticobasal syndrome (PSP-CBS). However, differences across the early presentations and their subsequent clinical courses remain to be elucidated.

This study aimed to characterize early PSP subtypes and their subsequent progressions using a large postmortem dataset.

An automated pipeline incorporating fine-tuned Chat Generative Pretrained Transformer (ChatGPT) was developed. The pipeline collected 195 clinical features with onset information from autopsy-confirmed PSP cases without significant neurodegenerative co-pathologies.

A structured clinicopathologic dataset from 588 patients was analyzed. The results from unsupervised clustering were distilled into a decision tree model. The mutually exclusive algorithm identified seven subtypes: PSP-PF (postural and frontal dysfunction), PSP-RS, PSP-PI, PSP-P, PSP-SL, PSP-F, and PSP-OM, based on five clinical manifestations: frontal presentation, postural instability, ocular motor dysfunction, speech/language disorder, and Parkinsonism. PSP-PF showed rapid progression, the shortest median disease duration (six years), and high tau burden in cortical and subcortical regions. In PSP-F, frontal presentation preceded other symptoms by four years, with a nine-year disease duration—second longest after PSP-P (10 years). PSP-CBS was not identified as an independent subtype.

This data-driven study identified a novel, aggressive PSP phenotype characterized by early postural and frontal dysfunction. Early subtyping using the decision tree model would help clinicians estimate progression and facilitate early patient recruitment for clinical trials.

The online version contains supplementary material available at 10.1007/s00415-025-13459-5.