Prevalence of progressive supranuclear palsy in Yonago: change throughout a decade

Abstract Background Progressive supranuclear palsy (PSP) is a neurodegenerative disorder that is sometimes confused with Parkinson's disease, multiple system atrophy, and other disorders. The typical clinical features are categorized as Richardson's syndrome (RS), but other clinical subtypes include PSP‐parkinsonism (PSP‐P) and PSP‐pure akinesia with gait freezing (PSP‐PAGF). In this study, we determined the prevalence of PSP in a Japanese rural area compared to our previous 1999 report. Methods We collected data in Yonago City from 2009 to 2014 using a service‐based study of PSP. We collected case history data from PSP patients in the area from our hospital. The crude prevalence and 95% confidence interval (CI) were calculated using the population demographics on the prevalence day of 1 October 2010. Age‐ and sex‐adjusted prevalence was calculated by direct standardization to the population demographics in Yonago City on the prevalence day of 1 April 1999. Material and Results We identified 25 patients: 16 with probable RS, 4 with possible RS, 3 with clinical PSP‐P, and 2 with clinical PSP‐PAGF. The prevalence per 100,000 was 17.90 (male = 18.05; female = 17.76). The prevalence of PSP in Yonago in 2010 increased compared to the measurements from 1999. Conclusion The prevalence of PSP in Japan increased from 1999 to 2010.


| Area of investigation
The investigated area, Yonago City, is located in western Japan ( ing as a neurologist at the University Hospital and continue to work closely with the University Hospital, as such, the neurological medical services in the area are quite efficient. Typical cases of Parkinson's disease or Alzheimer's disease were occasionally diagnosed at the general hospital. However, most atypical cases or severe cases with parkinsonism or motor symptom patients such as PSP, multiple system atrophy, corticobasal degeneration and amyotrophic lateral sclerosis were referred to the University Hospital, where they underwent detailed examination and diagnosis. The subjects living in the area of former Yonago City were analyzed according to the population demographics generated from the former Yonago City in order to use the same area for comparison with the prevalence of PSP in 1999.

| Service-based study in Yonago City
The survey was performed six times over 6 years from 2009 to 2014.
In each survey, case data were collected from the medical records of PSP, Parkinson's disease, corticobasal degeneration, multiple system atrophy, and Parkinson's syndrome patients at the University Hospital.

| Diagnosis
The patients participated in an interview regarding their clinical information, including symptoms, clinical course, past history, family history, a detailed neurological examination by board-certified neurologists, and more examinations (including a magnetic resonance imaging study and 123-I-meta-iodobenzylguanidine myocardial scintigraphy in the Division of Neurology at Tottori University Hospital).
RS was diagnosed according to the criteria of the NINDS-SPSP. We researched in detail the clinical history of the patients who conformed to the criteria of possible PSP with symptoms of vertical supranuclear palsy or slowing of vertical saccades, but not prominent postural instability with falls occurring in the first year. Subtypes of PSP were classified according to the reports by Williams et al., (2005Williams et al., ( , 2007. PSP-P was clinically diagnosed if the patient demonstrated the clinical features of asymmetric onset, tremor, and a moderate initial therapeutic response to levodopa. For patients with possible PSP, we diagnosed cases with a Parkinson's disease-like clinical picture with a moderate levodopa response in the first 2 years as clinical PSP-parkinsonism (cPSP-P). For possible PSP, we diagnosed cases with gradual onset of gait freezing or speech impairment, an absence of limb rigidity, no dementia, or ophthalmoplegia during the first 5 years, and no sustained response to levodopa as clinical PSP-pure akinesia with gait freezing (cPSP-PAGF).

| Data analysis
The prevalence day was defined as the date when the number of PSP patients became constant in terms of the change in initial registrations and deaths of the patients. The crude prevalence per 100,000 living people and the 95% confidence interval (CI) were calculated using the population demographics generated from the former Yonago City on the prevalence day of 1 October 2010. The prevalence of each clinical PSP subtype was calculated for the same time. Age-and sex-adjusted prevalence was calculated by direct standardization to the population demographics in Yonago City on the prevalence day of 1 April 1999 and in Japan on the prevalence day of 1 October 2010. In the present study, we used the same clinical diagnostic criteria for PSP that was used in a previous report by Kawashima, et al., (2004). The prevalence of RS (probable RS and possible RS) and PSP (RS, cPSP-P, and cPSP-PAGF) were compared between the April 1, 1999 and During this investigation period, before the prevalence day of 1 October 2010, one patient with probable RS died. After the prevalence day, 11 patients died. Three cases were confirmed pathologically as definite PSP. Table 1 summarizes the characteristics of the three autopsied PSP cases. Case 1 was diagnosed as cPSP-P, case 2 and case 3 were diagnosed as probable RS. The period from onset to diagnosis of PSP was 3.2 ± 2.5 years.

| DISCUSSION
This is the first report to investigate the change (during a decade) in the prevalence of PSP using the same surveillance area in Japan. The prevalence of PSP per 100,000 people in Yonago City in 2010 was 17.90 (male = 18.05; female = 17.76). Our present data indicated that the prevalence of PSP per 100,000 people in Yonago City increased compared to 1999 (Kawashima et al., 2004) in which it was 5.82 (male = 9.14; female = 2.75), and the 95% CI was 1.78-9.86 (male = 1.82-16.47; female = −1.08-6.65) (Fig. 1). In the comparison for Yonago City, the age-and sex-adjusted prevalence per 100,000 people in Yonago City on the prevalence day of 1 April 1999 was 11.92 (male = 11.66; female = 13.25), and the 95% CI was 7.38-19.25 (male = 5.83-23.33; female = 7.01-24.76). The number of patients with PSP increased even if adjusted by age and sex. When including only RS, the prevalence of PSP per 100,000 people in Yonago City was greater in 2010 compared to the 1999 study (Fig. 1) (Williams et al., 2005), PSP-PNFA (Williams et al., 2005), and PSP-C (Kanazawa et al., 2009), have been reported, no patients were diagnosed with these subtypes in this study.
The prevalence of PSP has also been reported in areas outside of Japan. In several population-based studies in various countries, reports of PSP prevalence vary from 1.0 to 6.5 per 100,000 people (Chio, Magnani, & Schiffer, 1998;Golbe, Davis, Schoenberg, & Duvoisin, 1988;Nath et al., 2001;Schrag, Ben-Shlomo, & Quinn, 1999;Wermuth, Joensen, Bunger, & Jeune, 1997), which is in agreement with the results of our previous report: 5.82 per 100,000 people (Kawashima et al., 2004). However, the prevalence of PSP in Kochi, Japan, reported by Osaki, Morita, Kuwahara, Miyano, & Doi (2011) was 18 per 100,000 people, and the age-and sex-adjusted prevalence per 100,000 people in Japan was 10 per 100,000 with a 95% CI of 2-17. These subjects had RS, but the authors did not include patients with PSP-P or PSP-PAGF.
In that study, the crude prevalence of RS was higher compared to our data. However, when adjusted for age and sex, the adjusted prevalence was lower compared to our data. This indicates that the difference between the two studies may be due to the proportion of the population in the investigated area and the survey method.
We observed almost identical rates for both sexes (12 males and 13 females), which was inconsistent with our previous report (6 male vs. survey. Clinical diagnoses of PSP-P or PSP-PAGF were not allowed due to the lack of clinical criteria, therefore in this study we provide new criteria for cPSP-P and cPAGE. Further investigation will be required to determine the accuracy of these clinical criteria using confirmed pathological cases. In this study, the participants were diagnosed via detailed neurological examinations by multiple neurological specialists at the University Hospital and were evaluated via magnetic resonance imaging of the brain and by 123-I-meta-iodobenzylguanidine myocardial scintigraphy, which effectively differentiates PSP from Parkinson's disease (Braune, Reinhardt, Schnitzer, Riedel, & Lucking, 1999;Orimo, Ozawa, Nakade, Sugimoto, & Mizusawa, 1999;Rascol & Schelosky, 2009). Therefore, the diagnostic accuracy was high. This study was an investigation conducted Crude prevalence rate Age-and sex-adjusted prevalence rate PSP/RS (per 100,000 population) PSP/RS in 1999 (Kawashima et al., 2003) PSP in 2010 (present study) RS in 2010 (present study) through medical institutions, and some patients with PSP were not able to be contacted for this survey. Given that some patients were not referred to the University Hospital from the general hospital, it is possible that referral bias might exist in this study. Moreover, some patients that underwent medical treatment at home may not have been included in this investigation because the design of this investigation was not a door-to-door study. Epidemiologic problems, such as immigration to other cities or being diagnosed at other hospitals out of this region, are other factors that may have excluded some patients. Patients with PSP may be admitted to nursing homes without visiting neurologists or with a misdiagnosis because PSP is insidious in onset and progresses slowly.
PSP is currently difficult to diagnose. Most patients who were diagnosed with rare neurodegenerative diseases, such as PSP, visited the University Hospital for diagnosis more than one during their clinical course around the Yonago area. In this study, the period from onset to diagnosis of PSP was approximately 3 years, whereas this investigation was conducted over 6 years. Investigating for a long period prevented PSP patients from dropping out of this study. We believe that our data include most of the patients with PSP in the investigational area.
In conclusion, the prevalence of PSP in Yonago City, Japan, increased during the 11-year period from 1999 to 2010. The increased prevalence of PSP in 2010 might be due to several factors, including the aging population. The adjusted prevalence of RS per 100,000 people in 2010 was still greater than the prevalence of PSP per 100,000 people in 1999. The increasing prevalence of PSP may be due not only to population aging but also to the inclusion of other phenotypes or the improved awareness of the condition. PSP was certified by the Specified Disease Treatment Research Program of the Japanese government in 2003, which subsidizes medical care for patients with rare and intractable diseases. An increase in PSP diagnoses may be due to the improvement in social systems, allowing for better patient identification.