To the best of our knowledge, this paper is the first to consider the neuroimaging biomarker M/P area ratio as a predictor for prognosis and to explore the factors associated with the progression of disability of living. In this paper, we found that predictors associated with poorer survival and earlier institutionalization were older age at onset and decreased M/P area ratio.
In the survival analysis, decreased M/P area ratio was associated with earlier death and institutionalization. Paviour et al found that M/P area ratio was smaller in PSP than Parkinson’s disease, multiple system atrophy or controls . The phenomenon that midbrain atrophy progressed in PSP-RS and PSP-P was observed in previous researches [15, 17]. Previous studies found that brainstem atrophy rates, especially the change in the midbrain volume were correlated with disease progression measured by PSP Rating Scale [18-21]. Inability to move eyes downward early was observed to predict survival time and midbrain atrophy predicted the disease progression of supranuclear gaze palsy[14, 22]. These researches indicated that M/P area ratio may be related to progression of motor disability and death risk in PSP. Axial symptoms may influence the survival time and it is also associated with pathological change in the brainstem, especially in the midbrain, thus they are associated with a smaller midbrain volume. Besides, the correlations were identified in previous studies between midbrain volume and motor disability and between PSPRS scores and [18F]AV-1451 uptake in the midbrain, indicating that pathological change in midbrain might predicted severer disease[16, 23]. Thus, it might be useful as a progression marker in clinical trial for PSP.
In accordance with most previous studies, older age at onset is associated with shorter survival[6-9, 24]. But other few studies have found negative or inverse association between AAO and survival time[22, 25]. Shorter survival and institutionalization for people were expected for the elderly, regardless of disease. In our study, we also observed older AAO was a predictor for early institutionalization, which means patients with older AAO is associated with more rapid progression in motor disability. Consistent with our results, Golb et al found that patients with older AAO has a higher PSP rating scale score and progressing more rapidly.
Few studies investigated the association between urinary incontinence and survival time, though it was one of the prevalent autonomic symptoms in PSP[25-27]. In our study, we found the association between incontinence and survival and institutionalization in univariate model, but the association became negative in multivariate model. Rare studies explored the association between apathy and prognosis in PSP despite that apathy is a common psychiatric symptom in PSP. In our study, we found that apathy was associated with death and institutionalization in earlier institutionalization in univariate model, but the association became negative in multivariate model. But the sample of our study was small, larger sample is needed to verify our results.
Inconsistent with previous studies found that RS phenotype was associated with a worse prognosis [4, 5, 8], there was no significant association found between phenotype and prognosis with K-M method or Cox proportional hazard model in our study. The reasons for the inconsistence are as followings. Previous studies mostly compared PSP-RS phenotype versus PSP-P phenotype while non-RS phenotype explored in our study included PSP-P, PSP-F and PSP-FOG. Published studies found that the median survival time of patients with PSP-F was similar with PSP-RS and its cumulative mortality after 5 years was mildly higher than PSP-RS [28-30]. The dementia and frontal symptoms, the most common features in PSP-F, were associated with earlier death[26, 31]. A recently published study found cognitive impairment in PSP, especially executive dysfunction, was associated with severity of PSP-related tau pathology in autopsy-confirmed PSP patients, which might explain the association with poorer prognosis. After excluding PSP-F and PSP-FOG, we found that a trend for the association of PSP-P with a longer survival. The small number of our sample may also influence our results. Thus, a larger sample with various phenotype is needed for further exploration. Besides, the MDS-PSP criteria was used in this study, while previous studies using NINDS-SPSP. This difference of two diagnosis criteria may account for the negative results to some extent.
Furthermore, unlike in previously published articles, the criteria for diagnosis and classification in the study was MDS-PSP rather than NINDS-SPSP. Respondek et al found that the sensitivity of NINDS-SPSP to detect non-RS phenotype was relatively unsatisfactory. MDS-PSP is based on NINDS-SPSP added akinesia and cognitive dysfunction besides ocular motor dysfunction, postural instability as core symptoms, thus leading to the improved detection for non-RS phenotype.
The strength of our study are as follows: 1）the present study is the first one to investigate the association between neuroimaging and the prognosis in PSP; 2) in addition to explore the factors associated with early death, we also explored the factors associated with early institutionalization to find out what factors influence progression of disability; 3) some non-motor symptoms including apathy and urinary incontinence rarely mentioned in previous studies were included in our research to explore their role on survival and progression in PSP; 4) MDS-PSP criteria was used in our study to contain a wider spectrum of PSP.
Our study has several limitations. First, this was a retrospective study based on medical history and interview. The information of medical history may be less accurate for the biased memory of patients and incomplete medical history interviewed by doctor. However, the information was completed by movement disorder specialists and reconfirmed by a structured interview with the patient or their caregivers, making it more accurate. Secondly, the sample in our study was relatively small. However, PSP is a rare disease per se. Thirdly, the diagnosis was made by clinical criteria. However, the patients enrolled fulfilled the probable and possible PSP of PSP-MDS criteria which has relatively high specificity . Besides, the mean interval between onset of symptoms and MRI was 3.8 years, which was a long time, since atypical clinical features and structural neuroimaging findings may not appear in the early disease course, interfering the diagnosis of PSP. Thus, an early neuroimaging marker are needed.