|dc.identifier.citation||Edwin Jabbari; Negin Holland; Viorica Chelban; P. Simon Jones; Ruth Lamb; Charlotte Rawlinson; Tong Guo, PhD; Alyssa A. Costantini, BSc; Manuela M. X. Tan, BPsych; Amanda J. Heslegrave, PhD; Federico Roncaroli, FRCPath, PhD; Johannes C. Klein, MD, PhD; Olaf Ansorge, FRCPath, PhD; Kieren S. J. Allinson, FRCPath, PhD; Zane Jaunmuktane, FRCPath; Janice L. Holton, FRCPath, PhD; Tamas Revesz, FRCPath, PhD; Thomas T.Warner, FRCP, PhD; Andrew J. Lees, FRCP, FMedSci; Henrik Zetterberg, PhD; Lucy L. Russell, BSc; Martina Bocchetta, PhD; Jonathan D. Rohrer, MRCP, PhD; Nigel M. Williams, PhD; Donald G. Grosset, MD; David J. Burn, FRCP, PhD; Nicola Pavese, FRCP, PhD; Alexander Gerhard, MD; Christopher Kobylecki, FRCP, PhD; P. Nigel Leigh, FRCP, PhD; Alistair Church, MRCGP; Michele T. M. Hu, FRCP, PhD; John Woodside; Henry Houlden, FRCP, PhD; James B. Rowe, FRCP, PhD; Huw R. Morris, FRCP, PhD Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome. JAMA Neurology, Dec 20 2019||en
|dc.description.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.||en