Progressive supranuclear palsy (PSP) is an atypical parkinsonian syndrome associated with a specific four repeat (4R) tau neuropathology at autopsy. The classic movement disorder clinical phenotype now was referred to as Richardson’s syndrome (PSP-RS). It was first described in 1964 as a clinicopathological entity, characterized by vertical supranuclear gaze palsy, early postural instability with unprovoked falls, progressive axial rigidity, and mild dementia (Steele et al., 1964; Ling, 2016; Armstrong, 2018). Following its initial description, other phenotypes of PSP have been gradually described, known as the variant PSP (vPSP), which greatly broadened the clinical spectrum of PSP (Williams et al., 2005; Respondek et al., 2014; Owens et al., 2016; Höglinger et al., 2017). The cardinal neuropathologic features of PSP at autopsy included neurofibrillary tangles (hyperphosphorylated tau protein), along with neuronal loss and gliosis (Dickson et al., 2007). Second-generation tau tracers, such as ^[18F]MK-6240, ^[18F]PI-2620 and others, could be expected to be viable biomarkers for 4R tauopathies (Leuzy et al., 2019; Cassinelli Petersen et al., 2022). Tau PET imaging could enable in vivo visualization of PSP-related tau pathology, and play an important role in identifying PSP from atypical parkinsonisms (Jin et al., 2023).

PSP is a rare disease with an estimated prevalence of 3–6/100000 (Respondek et al., 2017); However, it is worth noting that this prevalence data mainly reflected the occurrence of PSP-RS (Stamelou et al., 2019). The true prevalence of PSP is likely underestimated due to insufficient recognition of vPSP. Among the different phenotypes, PSP-RS is the most common, followed by PSP-parkinsonism (PSP-P) (Alster et al., 2020). Although Movement Disorder Society new clinical diagnostic criteria for PSP (MDS-PSP) were published in 2017, aiming to include all PSP subtypes early, clinicians still have difficulties in diagnosing the vPSP phenotype (Höglinger et al., 2017; Ali et al., 2019).

There was a delay, usually 3 years, from the onset of symptoms to the diagnosis of PSP (Cui et al., 2020). That is halfway through the illness. PSP is a uniformly fatal disease without effective therapies, but treatment can be helpful. Moreover, potential disease-modifying therapies for PSP heighten the need for early, accurate clinical diagnosis (Boxer et al., 2017; Höglinger et al., 2017; Jabbari et al., 2020); therefore, early recognition and correct diagnosis of PSP is essential.

This study analyzed the clinical characteristics, disease progression, and MRI assessment of PSP patients in mainland China. Then, the characteristics between PSP-RS and PSP-P cases were compared. We aim to investigate the frequency of major clinical symptoms at different stages of PSP, identify easily accessible imaging parameters, and determine the predictors for early diagnosis in the clinic.

In this study, we systematically analyzed the clinical characteristics, disease progression and MRI assessment of PSP patients in mainland China. During disease progression, PSP-RS patients were more prone to falls and vertical ocular dysfunction, whereas PSP-P patients were more likely to develop tremors. By reflecting the MRI parameters of midbrain atrophy, it was confirmed that the midbrain atrophy in the PSP-RS group was more obvious than that in the PSP-P group. Longitudinal MRI changes were more pronounced in PSP-RS than in PSP-P. In addition, a series of midbrain-based MRI assessments would identify PSP-P from PD with good diagnostic accuracy.

There were 150 PSP patients in our cohort, including 100 PSP-RS patients, 44 PSP-P patients, and 6 other vPSP patients. The PSP-RS patients accounted for 66.7% of PSP cases in our cohort, while vPSP patients were for 33.3%. Respondek et al. found that vPSPs occurred in 60–75% of PSP cases in an autopsy-confirmed cohort (Respondek et al., 2014). This value was much higher than the ratio in our cohort. A potential explanation was that the typical features of vPSP did not exist, or it would only be apparent after a few years of disease (Respondek et al., 2017). This may lead to missed diagnosis of vPSP patients. As we observed, the disease duration of PSP-P patients was obviously longer. This was consistent with previous report that patients with PSP-P and PSP-progressive gait freezing (PSP-PGF) experienced a long delay in diagnosis, because they have similar clinical trajectory and initial clinical characteristics as PD (Jabbari et al., 2020). One study demonstrated that a number of patients (9.1%) with an initial diagnosis of PD developed PSP-P during a 4-year follow-up (Quattrone et al., 2019). By contrast, PSP-P and PSP-PGF were associated with slower rates of disease progression, which may also have led to a delay (Jabbari et al., 2019). There was a significant sex difference in our PSP cohort, with more men than women. This phenomenon might be explained by differences regarding sex-based comorbidities at a higher age or the lower life expectancy of older men (Chiu et al., 2010; Jecmenica-Lukic et al., 2014). Additionally, recent studies have proposed that sex-based differences exist in PSP regarding the clinical characteristics, progression, and survival of the disease (Mahale et al., 2022).

Then, clinical features and MRI image presentations between PSP-RS group and PSP-P group were further compared. Patients in the PSP-RS and PSP-P groups mainly exhibited distinct motor symptoms throughout the disease. The former was dominated by postural instability, and the latter by parkinsonism. Previous research found that the PSP-RS phenotype had a shorter interval from disease onset to clinical milestones—such as frequent falls, severe dysphagia, speech difficulties, and wheelchair dependence—while the PSP-P phenotype had a more favorable course and longer survival (O'Sullivan et al., 2008; Jecmenica-Lukic et al., 2014; Glasmacher et al., 2017). Moreover, the tau burden was significantly higher in the PSP-RS than PSP-P (Williams et al., 2007). In short, there were differences in PSP-P and PSP-RS in terms of pathological characteristics, clinical progress and prognosis. Thus, early diagnosis and detection of PSP-P is critical.

A series of midbrain-based MRI morphometric assessments have provided clues to differentiate PSP from other parkinsonian disorders. However, there have been relatively few studies of MRI assessment of different PSP phenotypes. Picillo et al. found that the midbrain area, MBTegm, and MTPR showed significant differences between patients with PSP-RS and vPSP (Picillo et al., 2020). It was comparable to our observations that PSP-RS had a lower midbrain diameter, MTPR, midbrain area, Ma/Pa, and MBTegm than PSP-P. Moreover, MRI biomarkers may be predictors of the prognosis and disease features of PSP. The MRPI accurately predicted the appearance of vertical supranuclear gaze palsy in patients with PSP-P, and reduced midbrain area was significantly associated with greater ocular motor dysfunction, more rapid disease progression, and earlier death (Quattrone et al., 2016; Cui et al., 2020; Picillo et al., 2020). Although MRI plays an important role in supporting the clinical diagnosis of PSP, longitudinal MRI studies involving patients with PSP in the early symptomatic phase were insufficient.

In our cohort, the longitudinal MRI changes were investigated in patients with PSP. The annual rel.ΔMTPR and rel.Δ (Ma/Pa) for PSP were 5.55 and 6.52%, respectively; additionally, PSP-RS presented a higher decline rate than PSP-P. The possible reason was that PSP-P patients presented with a slower rate of progression than PSP-RS. Previous longitudinal MRI studies reported that the relative 1-year decline in MTPR in patients with PSP was 4.74%, with greater midbrain atrophy in patients with PSP than in those with PD (Hwang et al., 2017; Kannenberg et al., 2021). Midbrain-based measurements, including the MRPI and MRPI 2.0 scores, progressed differently in PSP-RS and PSP-P (Quattrone et al., 2020); The rate of midbrain atrophy changes with disease progression requires further exploration. An interesting finding was that the two MRI scanning intervals of the patient were only half a year, but midbrain-based measurements changed significantly. Previous studied found that interval of 6 months could reveal imaging atrophy and clinical progression in PSP patients (Whitwell et al., 2012; Dutt et al., 2016). In total, the clinical evaluation and MRI examination of patients with atypical parkinsonian syndrome every six months were appropriate, which could help clinicians identify PSP. Longitudinal MRI studies involving more patients with PSP were essential for the discovery of potential in vivo imaging markers for early diagnosis.

As mentioned above, PSP-P was difficult to diagnose in the early stages and was frequently misdiagnosed as PD initially. They had similar clinical trajectories and initial clinical features but differed in their responses to treatment and prognosis. Early diagnosis and detection of PSP-P was critical. Our result was consistent with previous studies that midbrain-based MRI parameters had significantly decreased in the PSP-P group compared with those in the PD group (Alster et al., 2020). Moreover, among them, MTPR ≤0.56, midbrain diameter ≤ 0.92, midbrain area ≤ 1.00, and third ventricle width ≤ 0.75 could identify PSP-P from PD with good diagnostic accuracy. With the development of neuroimaging research, several single photon emission computed tomography (SPECT) studies have shown that the hypoperfusion subregions of cerebellar and frontal lobe were feasible in identifying PSP-P from MSA-P (Alster et al., 2022; Madetko-Alster et al., 2022). Future studies should verify these approaches in the larger cohort.

Our study has several limitations. Firstly, Information was mainly compiled from the medical history, which may be less accurate due to the biased memory of patients; however, movement disorder specialists have reconfirmed the information through structured interviews with the patients or their caregivers. Secondly, diagnoses were made based on clinical criteria, since we could not access pathologically-proven cases in this study; however, the enrolled patients who fulfilled the clinical criteria were diagnosed with possible or probable PSP with relatively high specificity. Thirdly, despite the fact that PSP is a rare disorder, the number of participants with PSP in our study was relatively small, especially in the vPSP patients. Additionally, the number of cases with longitudinal MRI images was small, and the intervals between the different cases varied; therefore, further studies with larger cohorts, including different PSP phenotypes, are warranted to identify biomarkers that support the clinical phenotypic categorization of patients with PSP.

This study with a relatively large PSP cohort suggested differences in clinical presentation, MRI and longitudinal MRI changes between PSP-P and PSP-RS, as well as MRI parameters that might serve as potential imaging markers to differentiate PSP-P from PD.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving humans were approved by the Ethics Committee of Xiangya Hospital, Central South University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

YW and QY: conceptualization, investigation, formal analysis, data curation, and writing – original draft. BJ, WZ, YaZ, QX, HZ, LW, XL, YuZ, JW, JG, XY, HJ, and BT: investigation and formal analysis. JL: formal analysis and writing – review and editing. LS: conceptualization, investigation, and writing – review and editing. All authors contributed to the article and approved the submitted version.

The study was supported by the National Key R&D Program of China (Nos. 2020YFC2008500, 2018YFC1312003), the National Natural Science Foundation of China (Nos. 81501110, 81671075, 81971029, 82071216, 81901171), National Major Projects in Brain Science and Brain-like Research (No. 2021ZD0201803), Hunan Innovative Province Construction Project (No. 2019SK2335), and the Youth Science Foundation of Xiangya Hospital (No. 2018Q020).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.