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 or multiple system atrophy or controls and motor disability was most strongly associated with midbrain volume in PSP. The phenomenon that midbrain atrophy progressed in PSP-RS and PSP-P was observed in previous researches [16, 18]. Previous studies found that brainstem atrophy rates were correlated with disease progression measured by PSP Rating Scale[19, 20]. Inability to move eyes downward early was observed to predict survival time and midbrain atrophy predicted the disease progression of supranuclear gaze palsy[15, 21]. 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 brainstem, especially in midbrain, thus they are associated with a smaller midbrain volume. Besides, previous studies found the volume of midbrain related with disease severity, indicating that pathological change in midbrain might predict more severe disease. Furthermore, it might also 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[3, 6, 9, 10, 22]. But other few studies have found negative or inverse association between AAO and survival time[5, 21]. Older AAO related to earlier death and institutionalization is consistent with interpretations that the older the patients are, the disease is more severe. Furthermore, shorter survival and mobile times 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 the group 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[5, 23, 24]. 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 explore the association between apathy and prognosis in PSP despite apathy is a common psychiatric symptom in PSP. In our study, we found that apathy is 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 is small, larger sample is needed to verify our results.
Inconsistent with previous studies describing that RS phenotype was associated with a worse prognosis[7, 8, 10], no significant association was found between phenotype and prognosis with K-M method or Cox proportional hazard model in our study. Reasons for the inconsistence we consider are as followings. One is that previous studies mostly compared PSP-RS phenotype versus PSP-P phenotype while non-RS phenotype 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 [25-27]. The dementia and frontal symptoms, the most common features in PSP-F, were also regarded associated with earlier death[4, 23]. 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, large 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 is MDS-PSP rather than NINDS-SPSP. Respondek et al found that the sensitivity of NINDS-SPSP to detect non-RS phenotype is relatively unsatisfactory. MDS-PSP 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 prognosis in PSP; 2) in addition to explore factors associated with early death, we also explore 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 are included in our research to explore their role on survival and progression in PSP; 4) MDS-PSP criteria is 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.We cannot know whether the symptoms did not occurred or were not asked or recorded if the symptoms were absent in the medical history. However, the information had been completed by movement disorder specialists; moreover, we confirm this information by a structured interview with the patient or main caregiver, making it more accurate. Second, the sample in our study was relatively small, however PSP is a rare disease per se. Third, 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, mean interval between onset of symptoms and MRI is 3,8 years, which is 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.