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    Original Investigation
    December 20, 2019

    Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome

    Author Affiliations
    • 1Department of Clinical and Movement Neurosciences, UCL (University College London) Queen Square Institute of Neurology, London, United Kingdom
    • 2Movement Disorders Centre, UCL Queen Square Institute of Neurology, London, United Kingdom
    • 3Department of Clinical Neurosciences and MRC (Medical Research Council) Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, United Kingdom
    • 4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom
    • 5UK Dementia Research Institute, UCL Queen Square Institute of Neurology, London, United Kingdom
    • 6Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, United Kingdom
    • 7Department of Neurology, Manchester Academic Health Science Centre, Salford Royal NHS (National Health Service) Foundation Trust, University of Manchester, Manchester, United Kingdom
    • 8Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
    • 9Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, United Kingdom
    • 10Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, United Kingdom
    • 11Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
    • 12Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
    • 13Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, United Kingdom
    • 14Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom
    • 15Departments of Geriatrics and Nuclear Medicine, Universitätsklinikum Essen, Essen, Germany
    • 16Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester, United Kingdom
    • 17Department of Neuroscience, Brighton and Sussex Medical School, Brighton, United Kingdom
    • 18Department of Neurology, Royal Gwent Hospital, Newport, United Kingdom
    JAMA Neurol. Published online December 20, 2019. doi:10.1001/jamaneurol.2019.4347
    Key Points

    Questions  What are the distinguishing features of progressive supranuclear palsy and corticobasal syndrome subtypes and how can they be distinguished from Parkinson disease?

    Findings  In this cohort study of 222 patients with atypical parkinsonian syndromes, recently defined progressive supranuclear palsy subtypes are almost as common as classic Richardson syndrome and share midbrain atrophy as a common hallmark. Distinct patterns of clinical trajectory, cognitive profile, serum neurofilament light chain level, genetic, and volumetric magnetic resonance imaging measures helped to distinguish the clinical subtypes of progressive supranuclear palsy and corticobasal syndrome; clinical trajectory and serum neurofilament light chain levels distinguished Parkinson disease from progressive supranuclear palsy and corticobasal syndrome.

    Meaning  This study suggests that subtypes of progressive supranuclear palsy and corticobasal syndrome have distinct characteristics that may enhance their early diagnosis.

    Abstract

    Importance  Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), may be difficult to distinguish in early stages and are often misdiagnosed as Parkinson disease (PD). The diagnostic criteria for PSP have been updated to encompass a range of clinical subtypes but have not been prospectively studied.

    Objective  To define the distinguishing features of PSP and CBS subtypes and to assess their usefulness in facilitating early diagnosis and separation from PD.

    Design, Setting, Participants  This cohort study recruited patients with APS and PD from movement disorder clinics across the United Kingdom from September 1, 2015, through December 1, 2018. Patients with APS were stratified into the following groups: those with Richardson syndrome (PSP-RS), PSP-subcortical (including PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (including PSP-frontal and PSP-CBS overlap subtypes), MSA-parkinsonism, MSA-cerebellar, CBS–Alzheimer disease (CBS-AD), and CBS–non-AD. Data were analyzed from February 1, through May 1, 2019.

    Main Outcomes and Measures  Baseline group comparisons used (1) clinical trajectory; (2) cognitive screening scales; (3) serum neurofilament light chain (NF-L) levels; (4) TRIM11, ApoE, and MAPT genotypes; and (5) volumetric magnetic resonance imaging measures.

    Results  A total of 222 patients with APS (101 with PSP, 55 with MSA, 40 with CBS, and 26 indeterminate) were recruited (129 [58.1%] male; mean [SD] age at recruitment, 68.3 [8.7] years). Age-matched control participants (n = 76) and patients with PD (n = 1967) were included for comparison. Concordance between the antemortem clinical and pathologic diagnoses was achieved in 12 of 13 patients with PSP and CBS (92.3%) undergoing postmortem evaluation. Applying the Movement Disorder Society PSP diagnostic criteria almost doubled the number of patients diagnosed with PSP from 58 to 101. Forty-nine of 101 patients with reclassified PSP (48.5%) did not have the classic PSP-RS subtype. Patients in the PSP-subcortical group had a longer diagnostic latency and a more benign clinical trajectory than those in PSP-RS and PSP-cortical groups. The PSP-subcortical group was distinguished from PSP-cortical and PSP-RS groups by cortical volumetric magnetic resonance imaging measures (area under the curve [AUC], 0.84-0.89), cognitive profile (AUC, 0.80-0.83), serum NF-L level (AUC, 0.75-0.83), and TRIM11 rs564309 genotype. Midbrain atrophy was a common feature of all PSP groups. Eight of 17 patients with CBS (47.1%) undergoing cerebrospinal fluid analysis were identified as having the CBS-AD subtype. Patients in the CBS-AD group had a longer diagnostic latency, relatively benign clinical trajectory, greater cognitive impairment, and higher APOE-ε4 allele frequency than those in the CBS–non-AD group (AUC, 0.80-0.87; P < .05). Serum NF-L levels distinguished PD from all PSP and CBS cases combined (AUC, 0.80; P < .05).

    Conclusions and Relevance  These findings suggest that studies focusing on the PSP-RS subtype are likely to miss a large number of patients with underlying PSP tau pathology. Analysis of cerebrospinal fluid defined a distinct CBS-AD subtype. The PSP and CBS subtypes have distinct characteristics that may enhance their early diagnosis.

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