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.

中文翻译：

---

进行性核上性麻痹和皮质基底节综合征的诊断。

重要性 非典型帕金森综合征 (APS)，包括进行性核上性麻痹 (PSP)、皮质基底综合征 (CBS) 和多系统萎缩 (MSA)，早期可能难以区分，经常被误诊为帕金森病 (PD)。PSP 的诊断标准已更新，涵盖一系列临床亚型，但尚未进行前瞻性研究。目的 明确 PSP 和 CBS 亚型的区别特征，并评估它们在促进早期诊断和与 PD 分离方面的作用。设计、设置、参与者 这项队列研究从 2015 年 9 月 1 日至 2018 年 12 月 1 日从英国各地的运动障碍诊所招募了 APS 和 PD 患者。APS 患者被分为以下几组：理查森综合征 (PSP) 患者-RS)、PSP-皮质下（包括 PSP-帕金森病和进行性步态冻结亚型）、PSP-皮质（包括 PSP-额叶和 PSP-CBS 重叠亚型）、MSA-帕金森病、MSA-小脑、CBS-阿尔茨海默病 (CBS- AD）和 CBS-非 AD。数据分析时间为2019年2月1日至5月1日。主要结果和措施使用基线组比较（1）临床轨迹；(2)认知筛查量表；(3)血清神经丝轻链(NF-L)水平；(4) TRIM11、ApoE和MAPT基因型；(5) 体积磁共振成像措施。结果 总共招募了 222 名 APS 患者（101 名 PSP、55 名 MSA、40 名 CBS 和 26 名不确定患者）（129 名 [58.1%] 为男性；招募时平均 [SD] 年龄为 68.3 [8.7] 岁）。年龄匹配的对照参与者 (n = 76) 和 PD 患者 (n = 1967) 被纳入比较。在接受尸检评估的 13 名 PSP 和 CBS 患者中，有 12 名 (92.3%) 的生前临床诊断与病理诊断一致。应用运动障碍协会 PSP 诊断标准，诊断为 PSP 的患者数量几乎翻了一番，从 58 名增加到 101 名。101 名重新分类的 PSP 患者中，有 49 名 (48.5%) 不具有经典的 PSP-RS 亚型。与 PSP-RS 和 PSP 皮质组患者相比，PSP 皮质下组患者的诊断潜伏期更长，临床轨迹更良性。PSP-皮质下组通过皮质体积磁共振成像测量（曲线下面积[AUC]，0.84-0.89）、认知概况（AUC，0.80-0.83）、血清NF- L 水平（AUC，0.75-0.83）和 TRIM11 rs564309 基因型。中脑萎缩是所有 PSP 群体的共同特征。接受脑脊液分析的 17 名 CBS 患者中，有 8 名 (47.1%) 被确定为 CBS-AD 亚型。与 CBS-非 AD 组患者相比，CBS-AD 组患者的诊断潜伏期更长、临床轨迹相对良性、认知障碍更严重、APOE-ε4 等位基因频率更高（AUC，0.80-0.87；P < .05 ）。血清 NF-L 水平可将 PD 与所有 PSP 和 CBS 病例相结合（AUC，0.80；P < .05）。结论和相关性这些发现表明，针对 PSP-RS 亚型的研究可能会漏掉大量具有潜在 PSP tau 病理学的患者。脑脊液分析确定了一种独特的 CBS-AD 亚型。PSP 和 CBS 亚型具有独特的特征，可以增强其早期诊断。