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Lookup NU author(s): Professor Nicola PaveseORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
© 2025 The Author(s).Atypical parkinsonian syndromes are distinguished from Parkinson's disease (PD) by additional neurological signs and characteristic underlying neuropathology. However, they can be diagnostically challenging, rapidly progressive and are often diagnosed late in disease course. Their different demographic features and prognoses are well studied, but the accompanying cognitive and psychiatric features may also facilitate diagnosis. Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) may cause cognitive and behavioural manifestations that overlap with frontotemporal dementia, including non-fluent aphasia, apathy and impulsivity. Clinical diagnostic criteria have limited sensitivity, with pathologically confirmed PSP often having presented an initial clinical syndrome other than PSP-Richardson's syndrome. Here, we integrate cross-sectional multicentre baseline data from the PROSPECT-M-UK and Oxford Discovery cohorts. This allowed us to compare cognitive and psychiatric features across a total of 1138 people with PSP, CBS, multiple-system atrophy (MSA) and idiopathic PD. Data from the different cohorts were harmonized and compared using multiple linear regression. There were five key results: (i) different syndromes showed distinctive cognitive profiles, using readily applicable 'bedside' screening tools. Frontal executive dysfunction was most evident in PSP, visuospatial deficits in CBS, with milder deficits in memory and executive function in MSA, as compared with PD; (ii) the most prevalent neuropsychiatric features were depression and anxiety in CBS, apathy in PSP, with sleep disturbances common in PD. As expected, apathy correlated positively with impulsivity across all disorders. Neuropsychiatric features were generally better at discriminating between atypical parkinsonian syndromes than were the cognitive domains; (iii) both cognitive function and motor severity declined with disease duration, and motor function predicted cognition in PSP, CBS and PD but not in MSA, suggesting that in MSA cognitive and motor dysfunction are decoupled; (iv) plasma neurofilament light chain (NFL) levels, measured in a subset of patients, correlated with cognitive deficits in PSP, but not motor deficits; (v) cognitive deficits contributed to the impairment in activities of daily living after controlling for motor severity, with every two points on the Montreal Cognitive Assessment worsening the Schwab and England score by one point. In anticipation of future neuroprotective therapies, we present a classifier to improve diagnostic accuracy for atypical parkinsonian syndromes in vivo. Longitudinal cohort studies with resources for neuropathological gold standard diagnosis remain important to validate better diagnostic tools for people with PSP, CBD, MSA and atypical parkinsonism.
Author(s): Hu MT, Coma AQ, Rowe JB, Zerenner T, Church A, Fumi R, Costantini A, Jabbari E, Jensen MT, Gerhard A, Pavese N, Kobylecki C, Leigh PN, Koychev I, Morris HR, Manohar SG
Publication type: Article
Publication status: Published
Journal: Brain
Year: 2025
Volume: 148
Issue: 9
Pages: 3239-3251
Print publication date: 01/09/2025
Online publication date: 16/04/2025
Acceptance date: 21/03/2025
Date deposited: 30/09/2025
ISSN (print): 0006-8950
ISSN (electronic): 1460-2156
Publisher: Oxford University Press
URL: https://doi.org/10.1093/brain/awaf132
DOI: 10.1093/brain/awaf132
Data Access Statement: De-identified data and a data dictionary will be made available following an application to the PROSPECT-M-UK Data Access committee (prospect@ucl.ac.uk), which will be reviewed by the data access committee, including PSP association representatives, independent chair and study principal investigators. The coefficients for the classifiers can be found online at https://osf.io/mz98x.
PubMed id: 40238956
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