RESEARCH
ARTICLE
Rate of Decline in Progressive Supranuclear Palsy Irene Litvan, MD,1* and Maiying Kong, PhD2 1
Movement Disorders Center, Department of Neurosciences, University of California San Diego, San Diego, California, USA 2 Department of Bioinformatics and Biostatistics, School Public Health and Information Sciences, University of Louisville, Louisville, Kentucky, USA
ABSTRACT:
The rate of patients’ decline is critical to properly design trials of disease-modifying agents. We prospectively quantified the progression of 27 progressive supranuclear palsy (PSP) patients for at least 1 year to determine the rate of decline of motor, ocular-motor, neuropsychological, and neuropsychiatric features. PSP patients meeting the National Institute of Neurological Disorders and the Society for Progressive Supranuclear Palsy criteria were assessed using the PSP Rating Scale (PSP-RS) and modified UPDRS. The Mini–Mental State Examination (MMSE) and Frontal Assessment Battery assessed cognitive decline, the Neuropsychiatric Inventory assessed behavior, and the modified Schwab and England scale and UPDRS ADL assessed activities of daily living (ADL). The rate of change of each score was calculated as 1-year worsening score. Power and sample sizes were estimated. PSP patients showed a significant yearly decline in total
PSP is a devastating sporadic neurodegenerative disorder with a relatively short survival time span that presents in middle- to late-age people with prominent postural instability, levodopa-unresponsive parkinsonism, dysarthia and dysphagia, frontal cogni-
------------------------------------------------------------
*Correspondence to: Irene Litvan, M.D., Movement Disorders Center, Department of Neurosciences, University of California San Diego, 8950 Villa La Jolla Drive, Suite C112, La Jolla, CA 92037, USA; [email protected]
Relevant conflicts of interest/financial disclosures: I.L. has been awarded grants from CurePSP and the National Institutes of Aging (5R01AG024040) and is employed by the University of California San Diego. M.K. has received honoraria from the University of Louisville and grant support from CurePSP. Full financial disclosure and author roles may be found in the online version of this article. Received: 1 January 2013; Revised: 30 December 2013; Accepted: 12 January 2014 Published online 24 February 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25843
and subtotal scores of the PSP-RS and UPDRS, as well as in MMSE, and UPDRS and Schwab and England ADL scores. In addition, they had significant deterioration of individual item scores reflecting major aspects of the disease (i.e., ocular-motor). The rate of decline reflected in the UPDRS mirrored that of the PSP-RS. The worsening of the ADL score was positively correlated with the PSP-RS progression of falls and ocularmotor subitem scores and with executive dysfunction. PSP patients showed a significant yearly decline in motor, ocular-motor, and ADL functions. Our findings suggest that using more-advanced technology to measure ocular-motor, postural instability, and ADL will be C 2014 Interhelpful in planning future therapeutic trials. V national Parkinson and Movement Disorder Society
K e y W o r d s : progressive supranuclear palsy; sample-size estimation; natural history
tive disturbances, slowing of vertical saccades, and, eventually, supranuclear vertical gaze palsy.1 Novel biological treatments for this primary tauopathy (mostly 4-repeat tau) have been identified in transgenic tau mice trials.2 However, trials of putative disease-modifying agents cannot be properly designed without knowledge of the natural history of patients’ decline. There are a few studies of the natural history of PSP.3-13 Previous studies surveyed caregivers of patients with PSP,6 retrospectively evaluated medical records of patients,3,7,9 some of whom were autopsyconfirmed cases,5,11 or, more recently, prospectively quantified the progression using the PSP-Rating Scale (PSP-RS)12 and Natural History and Neuroprotection in Parkinson Plus Syndromes scale.13 Valid estimates of change over a period of observation are critical for estimating sample size. Our current study was designed to prospectively determine the rate of decline of motor, neuropsychological, neuropsychiatric, and ocular-motor features of PSP patients recruited as part of R01 AG24040-01A2 and
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TABLE 1. Demographicsa
followed yearly for at least 1 year as part of a longitudinal study funded by the CurePSP Foundation.
Patients and Methods Sample Patients were eligible to participate if they met the National Institute of Neurological Disorders and the Society for Progressive Supranuclear Palsy (NINDSSPSP) research criteria, had no other central nervous system pathology, scored at least 24 on the Mini–Mental State Examination (MMSE),14 and were able to verbally communicate at the initial visit. A total of 31 of 46 eligible PSP patients recruited through the Movement Disorder Clinic at the University of Louisville (Louisville, KY) agreed to participate. Among the 15 eligible cases not recruited, 5 declined because of transportation difficulties, 7 were lost to follow-up, and 3 died before being recruited. Of the 31 patients enrolled in the study, we report on 27 with completed full neurological and neuropsychological evaluations from at least two yearly visits; 4 patients dropped out because they were unable to travel to the screening site.
Assessment A single movement disorder specialist (I.L.) assessed motor and ocular-motor features at yearly intervals in a standardized manner using the PSP-RS12 and the modified UPDRS for up to three yearly visits, including the first visit and at least 1-year follow-up. Cognition was assessed concomitantly using the MMSE and Frontal Assessment Battery (FAB),15 and behavior with the Neuropsychiatric Inventory (NPI).16 In addition, activities of daily living (ADL) were measured with the modified Schwab and England (S&E) ADL scale and UPDRS ADL.
Statistical Analysis Symptom worsening, indicated by increasing scores on the UPDRS, PSP-RS, and NPI, and decreasing scores of S&E ADL, MMSE, and FAB, were initially analyzed by plotting observations over time. Rates of progression of the UPDRS, PSP-RS, S&E ADL scale, MMSE, FAB, and NPI scores were estimated for individuals as well as for the entire group.17 The rate of progression of each score was calculated as 1-year worsening score. To control for variability in time elapsed between visits 1 and 2, as well as to optimally use the information provided in visit 3, the 1-year worsening score for a patient was obtained as the slope of the linear regression of the scores versus time elapsed since the first visit. The 1-year worsening score for the entire group was summarized from the individual 1-year worsening scores. We applied the Student one-sample t test to determine whether the 1-year worsening score was significantly different from zero18
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Demographics
Mean 6 SD or count (%)
Age at first visit, years Age at onset, years Duration from onset to first visit, years Gender, M/F Education, years High school High school diploma Technical or trade school diploma College diploma Graduate school diploma
65.3 6 7.9 62.2 6 8.0 3.1 6 1.7 15/12 (56/44) 14.7 6 3.5 5 (18.5) 6 (22.2) 1 (3.7) 5 (18.5) 10 (37.0)
a n 5 27. M, male; F, female.
and estimated 95% confidence intervals (CIs) for 1-year worsening scores (i.e., rate of progression). When the rate of progression was significantly different from zero, we examined its correlation with the rate of progression of other variables, as well as its correlation with the baseline motor, ocular-motor, bulbar, cognitive, and behavioral variables, using Pearson’s correlation coefficient.18 Significance level was adjusted by Bonferroni’s correction. We reported only correlations in which the adjusted P values were less than 0.05. When the rate of progression was significant, we also examined the sample size needed for a two-arm therapeutic trial that could slow decline by 50% and 25% in 1 year. Sample size was calculated based on the Student two-sample t test with a power of 80% and a significance level at 5%, and the variance for the two arms was assumed to be the variance estimated from this study.19
Results Demographic characteristics of the 27 PSP patients are summarized in Table 1. There were no differences between those having follow-ups and those that dropped out of the study in demographics except for age (participants were, overall, 5 years younger than nonparticipants; data not shown). Table 2 shows mean and standard deviation (SD) of the UPDRS, PSP-RS, and S&E scores for the first, second, and third visits; their group-level 1-year worsening scores, and the 95% CIs. Twenty-seven patients were followed for 1 year (mean 6 SD: 1.2 6 0.4), and among them, 5 were followed for 2 years (mean 6 SD: 2.0 6 0.3). The rate of progression of the UPDRS ADL, motor, and total scores and all the subtotal and total scores of the PSP-RS were significantly greater than zero. The rate of progression of the S&E ADL and MMSE were significantly less than zero. Progression rates of dysphagia for secretions, salivation, freezing, reading difficulties, ocular-motor function, and
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TABLE 2. Means and SD for scores at the first, second, and third visits, 1-year worsening scores, and their 95% CIs
Time elapsed from first visit (years) S&E ADL UPDRS Mental, Behavior and Mood ADL Motor Total UPDRS Dysphagia UPDRS Salivation UPDRS Swallowing UPDRS Freezing UPDRS Falls unrelated to freezing UPDRS Motor: Postural stability Reading PSP-RS History Mentation Bulbar Ocular Limb Gait Total PSP-RS Ocular-Motor Function
PSP-RS Falls PSP-RS Gait Postural stability PSP-RS Dysphagia While Eating MMSE Total Score FAB (z-score) NPI Score Total Score Nighttime behavior disorders Neurovegetative Symptoms Appetite and Eating Disorders
Upward Downward Left Right
First Visit Mean 6 SD (n 5 27)
Second Visit Mean 6 SD (n 5 27)
Third Visit Mean 6 SD (n 5 5)
Worsening Score Estimated 6 SD
95% CI for Worsening Score
75.9 6 14.7
1.2 6 0.4 54.8 6 16.9@
2.0 6 0.3 36.7 6 5.8^
214.9 6 18.8
[–22.7, 27.0]
3.0 6 1.9 16.8 6 5.5 23.3 6 7.3 43.1 6 10.6 0.9 6 1.1 1.1 6 0.9 1.5 6 0.8 1.0 6 1.4 2.0 6 1.1 1.9 6 0.6 1.4 6 0.8
3.5 6 1.6# 23.8 6 6.6 31.5 6 12.4# 57.5 6 18.4# 1.3 6 0.9# 1.6 6 1.2 1.7 6 0.9# 1.9 6 1.4 2.5 6 1.1 2.0 6 1.1^ 2.1 6 1.01
3.0 6 0.7 26.4 6 9.8 48.8 6 13 78.2 6 22.2 1.6 6 0.5 1.6 6 0.9 1.8 6 0.8 2.0 6 1.8# 3.0 6 1.4 3.2 6 0.8 2.4 6 0.5
0.2 6 1.8 6.0 6 5.5 6.3 6 9.2 11.4 6 13.2 0.4 6 1.1 0.4 6 0.9 0.1 6 0.7 0.9 6 1.2 0.4 6 1.1 0.1 6 0.9 0.5 6 0.8
9.0 6 2.3 1.8 6 1.5 2.4 6 1.4 8.2 6 3.2 3.9 6 1.7 8.3 6 4.1 33.5 6 7.5 2.7 6 1.2 2.7 6 1.3 0.8 6 0.8 0.8 6 0.8 2.8 6 1.3 2.3 6 1.0 1.1 6 0.7 27.9 6 1.6 23.6 6 3.1 8.8 6 8.8* 3 6 4* 2.5 6 3.4Ø
10.6 6 3.2 4.0 6 2.2 3.1 6 1.4 11.4 6 3.3# 5.2 6 1.7# 11.7 6 4.9# 44.9 6 12.2 3.7 6 0.8# 3.6 6 0.6# 1.4 6 1.0# 1.6 6 1.2# 3.4 6 0.9 2.5 6 1.4# 1.4 6 0.7# 25.5 6 2.6^ 24.9 6 4.0^ 9.4 6 7.4@ 2.6 6 4.2@ 2.4 6 3.8@
10.2 6 1.8 4.2 6 3.0 4.0 6 1.0 13.2 62.9 7.6 6 5.5 15.6 6 4.8 54.8 6 15.2 460 460 1.8 6 1.3 1.8 6 1.3 460 3.6 6 0.5 1.6 6 0.9 24.6 6 4.4 27.2 6 3.4 4.0 6 3.6^ 0 6 0^ 4.0 66.9^
1.5 6 3.3 1.9 6 2.2 0.6 6 1.4 2.8 6 1.7 1.1 6 1.5 2.6 6 3.2 9.1 6 9.4 0.7 6 0.9 0.7 6 1.1 0.6 6 0.6 0.7 6 0.7 0.5 6 1.3 0.1 6 1.2 0.2 6 0.6 22.1 6 1.7 21.1 6 3.7 1.5 6 6.6 20.1 6 3.9 0.2 6 2.4
[–0.5, 0.9] [4.0, 8.1] [2.8, 9.8] [6.4, 16.3] [0.0, 0.8] [0.1, 0.8] [–0.1, 0.4] [0.4, 1.3] [0.0, 0.9] [–0.2, 0.5] [0.1, 0.8] [0.2, 2.7] [1.0, 2.7] [0.1, 1.2] [2.1, 3.4] [0.6, 1.7] [1.3, 3.8] [5.6, 12.7] [0.4, 1.1] [0.3, 1.1] [0.4, 0.8] [0.4, 1.0] [0.1, 1.0] [–0.4, 0.6] [0.0, 0.5] [–2.8, 21.4] [–2.5, 0.4] [–1.3, 4.3] [–1.7, 1.6] [–0.9, 1.4]
The number of observations at first and second visits was 27 and at the third visit was 5, unless otherwise identified by the following: # 5 1 missing; ^ 5 2 missing; *3 missing; 15 missing; @ 5 6 missing; and Ø 5 7 missing. On the UPDRS, PSP-RS, and NPI, positive change scores indicate worsening. On the S&E, MMSE, and FAB, negative scores indicate worsening.
falls were significantly larger than zero. The rate of progression of postural stability was not significantly different from zero. Table 3 shows the significant associations between progression rates and baseline variables as well as between the various worsening progression-rate variables. For example, the UPDRSADL progression rate was positively correlated with the progression of falls and with the baseline PSP-RS ocular motor score.
Sample-Size Estimation Table 4 shows sample sizes required for a two-arm 1-year follow-up therapeutic trial to detect 25% and 50% improvements, respectively, with a power at 80% and a significance level at 5%, assuming the same SD for both groups. The SD and amount of improvement for each variable were assumed to be known and obtained from Table 2. The sample size in Table 4
reflects the required sample size per group before adjusting for expected dropout. If we apply the typical 20% adjustment, then the sample size for PSP-RS ocular-motor subitems would be 32 (i.e., 25/0.8 5 32) per group for a 50% reduction of the progression rate. In PSP, however, the dropout rate is likely to be higher. If one assumes a drop-out rate of 30%, the required sample size would be 36 (i.e., 25/0.7 5 36) per group.
Discussion This longitudinal prospective study of 27 PSP patients showed a significant yearly decline in motor (total and subtotal scores of the PSP-RS and UPDRS motor and total scores), cognitive (MMSE), and ADL functions (UPDRS ADL and S&E scores). Previous studies have mostly focused on total scale scores, but we found that the decline was not only significant in
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TABLE 3. Significant associations between progression rates and baseline variables Worsening Score
S&E ADL
UPDRS Total ADL Score UPDRS Total Motor Score
UPDRS Total Score
PSP-RS Total History Score PSP-RS Total Bulbar Score PSP-RS Total Ocular Score PSP-RS Total Gait Score
PSP-RS Total Score
PSP-RS Dysphagia for secretions PSP-RS Dysphagia While Eating PSP-RS Voluntary Downward Saccades
PSP-RS Voluntary Left Saccades PSP-RS Falls UPDRS Falls
Worsening Score/Baseline
Correlation Coefficient
Adjusted P Value
PSP-RS Postural Instability PSP-RS Total Gait FAB z-score UPDRS Falls Baseline PSP-RS Total Ocular Score UPDRS Falls Total UPDRS Score Baseline NPI Neurovegetative SymptomsAppetite and Eating Disorders UPDRS Postural Instability UPDRS Total Mentation, Behavior, Mood Score UPDRS Total Motor Score PSP-RS Total Score PSP-RS Falls PSP-RS Postural Instability PSP-RS Dysphagia Baseline PSP-RS Total Bulbar Score PSP-RS Voluntary Downward Saccades UPDRS Falls UPDRS Postural Instability PSP-RS Postural Instability S&E UPDRS Postural Instability PSP-RS Postural Instability UPDRS Total Score PSP-RS Total Gait PSP-RS Total Bulbar Baseline PSP-RS Dysphagia for Secretions UPDRS Swallowing PSP-RS Voluntary Upward Saccades PSP-RS Total Ocular Baseline PSP-RS Voluntary Downward Saccades PSP-RS Voluntary Right Saccades Baseline PSP-RS Total History PSP-RS Total History Baseline PSP-RS Falls UPDRS Total ADL PSP-RS Total Gait Baseline UPDRS Falls Baseline PSP-RS Total Ocular
20.781 20.770 0.707 0.706 0.625 0.650 0.863 20.732
0.0012 0.0019 0.0229 0.0026 0.0331 0.0298
ARTICLE
Rate of Decline in Progressive Supranuclear Palsy Irene Litvan, MD,1* and Maiying Kong, PhD2 1
Movement Disorders Center, Department of Neurosciences, University of California San Diego, San Diego, California, USA 2 Department of Bioinformatics and Biostatistics, School Public Health and Information Sciences, University of Louisville, Louisville, Kentucky, USA
ABSTRACT:
The rate of patients’ decline is critical to properly design trials of disease-modifying agents. We prospectively quantified the progression of 27 progressive supranuclear palsy (PSP) patients for at least 1 year to determine the rate of decline of motor, ocular-motor, neuropsychological, and neuropsychiatric features. PSP patients meeting the National Institute of Neurological Disorders and the Society for Progressive Supranuclear Palsy criteria were assessed using the PSP Rating Scale (PSP-RS) and modified UPDRS. The Mini–Mental State Examination (MMSE) and Frontal Assessment Battery assessed cognitive decline, the Neuropsychiatric Inventory assessed behavior, and the modified Schwab and England scale and UPDRS ADL assessed activities of daily living (ADL). The rate of change of each score was calculated as 1-year worsening score. Power and sample sizes were estimated. PSP patients showed a significant yearly decline in total
PSP is a devastating sporadic neurodegenerative disorder with a relatively short survival time span that presents in middle- to late-age people with prominent postural instability, levodopa-unresponsive parkinsonism, dysarthia and dysphagia, frontal cogni-
------------------------------------------------------------
*Correspondence to: Irene Litvan, M.D., Movement Disorders Center, Department of Neurosciences, University of California San Diego, 8950 Villa La Jolla Drive, Suite C112, La Jolla, CA 92037, USA; [email protected]
Relevant conflicts of interest/financial disclosures: I.L. has been awarded grants from CurePSP and the National Institutes of Aging (5R01AG024040) and is employed by the University of California San Diego. M.K. has received honoraria from the University of Louisville and grant support from CurePSP. Full financial disclosure and author roles may be found in the online version of this article. Received: 1 January 2013; Revised: 30 December 2013; Accepted: 12 January 2014 Published online 24 February 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25843
and subtotal scores of the PSP-RS and UPDRS, as well as in MMSE, and UPDRS and Schwab and England ADL scores. In addition, they had significant deterioration of individual item scores reflecting major aspects of the disease (i.e., ocular-motor). The rate of decline reflected in the UPDRS mirrored that of the PSP-RS. The worsening of the ADL score was positively correlated with the PSP-RS progression of falls and ocularmotor subitem scores and with executive dysfunction. PSP patients showed a significant yearly decline in motor, ocular-motor, and ADL functions. Our findings suggest that using more-advanced technology to measure ocular-motor, postural instability, and ADL will be C 2014 Interhelpful in planning future therapeutic trials. V national Parkinson and Movement Disorder Society
K e y W o r d s : progressive supranuclear palsy; sample-size estimation; natural history
tive disturbances, slowing of vertical saccades, and, eventually, supranuclear vertical gaze palsy.1 Novel biological treatments for this primary tauopathy (mostly 4-repeat tau) have been identified in transgenic tau mice trials.2 However, trials of putative disease-modifying agents cannot be properly designed without knowledge of the natural history of patients’ decline. There are a few studies of the natural history of PSP.3-13 Previous studies surveyed caregivers of patients with PSP,6 retrospectively evaluated medical records of patients,3,7,9 some of whom were autopsyconfirmed cases,5,11 or, more recently, prospectively quantified the progression using the PSP-Rating Scale (PSP-RS)12 and Natural History and Neuroprotection in Parkinson Plus Syndromes scale.13 Valid estimates of change over a period of observation are critical for estimating sample size. Our current study was designed to prospectively determine the rate of decline of motor, neuropsychological, neuropsychiatric, and ocular-motor features of PSP patients recruited as part of R01 AG24040-01A2 and
Movement Disorders, Vol. 29, No. 4, 2014
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L I T V A N
A N D
K O N G
TABLE 1. Demographicsa
followed yearly for at least 1 year as part of a longitudinal study funded by the CurePSP Foundation.
Patients and Methods Sample Patients were eligible to participate if they met the National Institute of Neurological Disorders and the Society for Progressive Supranuclear Palsy (NINDSSPSP) research criteria, had no other central nervous system pathology, scored at least 24 on the Mini–Mental State Examination (MMSE),14 and were able to verbally communicate at the initial visit. A total of 31 of 46 eligible PSP patients recruited through the Movement Disorder Clinic at the University of Louisville (Louisville, KY) agreed to participate. Among the 15 eligible cases not recruited, 5 declined because of transportation difficulties, 7 were lost to follow-up, and 3 died before being recruited. Of the 31 patients enrolled in the study, we report on 27 with completed full neurological and neuropsychological evaluations from at least two yearly visits; 4 patients dropped out because they were unable to travel to the screening site.
Assessment A single movement disorder specialist (I.L.) assessed motor and ocular-motor features at yearly intervals in a standardized manner using the PSP-RS12 and the modified UPDRS for up to three yearly visits, including the first visit and at least 1-year follow-up. Cognition was assessed concomitantly using the MMSE and Frontal Assessment Battery (FAB),15 and behavior with the Neuropsychiatric Inventory (NPI).16 In addition, activities of daily living (ADL) were measured with the modified Schwab and England (S&E) ADL scale and UPDRS ADL.
Statistical Analysis Symptom worsening, indicated by increasing scores on the UPDRS, PSP-RS, and NPI, and decreasing scores of S&E ADL, MMSE, and FAB, were initially analyzed by plotting observations over time. Rates of progression of the UPDRS, PSP-RS, S&E ADL scale, MMSE, FAB, and NPI scores were estimated for individuals as well as for the entire group.17 The rate of progression of each score was calculated as 1-year worsening score. To control for variability in time elapsed between visits 1 and 2, as well as to optimally use the information provided in visit 3, the 1-year worsening score for a patient was obtained as the slope of the linear regression of the scores versus time elapsed since the first visit. The 1-year worsening score for the entire group was summarized from the individual 1-year worsening scores. We applied the Student one-sample t test to determine whether the 1-year worsening score was significantly different from zero18
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Movement Disorders, Vol. 29, No. 4, 2014
Demographics
Mean 6 SD or count (%)
Age at first visit, years Age at onset, years Duration from onset to first visit, years Gender, M/F Education, years High school High school diploma Technical or trade school diploma College diploma Graduate school diploma
65.3 6 7.9 62.2 6 8.0 3.1 6 1.7 15/12 (56/44) 14.7 6 3.5 5 (18.5) 6 (22.2) 1 (3.7) 5 (18.5) 10 (37.0)
a n 5 27. M, male; F, female.
and estimated 95% confidence intervals (CIs) for 1-year worsening scores (i.e., rate of progression). When the rate of progression was significantly different from zero, we examined its correlation with the rate of progression of other variables, as well as its correlation with the baseline motor, ocular-motor, bulbar, cognitive, and behavioral variables, using Pearson’s correlation coefficient.18 Significance level was adjusted by Bonferroni’s correction. We reported only correlations in which the adjusted P values were less than 0.05. When the rate of progression was significant, we also examined the sample size needed for a two-arm therapeutic trial that could slow decline by 50% and 25% in 1 year. Sample size was calculated based on the Student two-sample t test with a power of 80% and a significance level at 5%, and the variance for the two arms was assumed to be the variance estimated from this study.19
Results Demographic characteristics of the 27 PSP patients are summarized in Table 1. There were no differences between those having follow-ups and those that dropped out of the study in demographics except for age (participants were, overall, 5 years younger than nonparticipants; data not shown). Table 2 shows mean and standard deviation (SD) of the UPDRS, PSP-RS, and S&E scores for the first, second, and third visits; their group-level 1-year worsening scores, and the 95% CIs. Twenty-seven patients were followed for 1 year (mean 6 SD: 1.2 6 0.4), and among them, 5 were followed for 2 years (mean 6 SD: 2.0 6 0.3). The rate of progression of the UPDRS ADL, motor, and total scores and all the subtotal and total scores of the PSP-RS were significantly greater than zero. The rate of progression of the S&E ADL and MMSE were significantly less than zero. Progression rates of dysphagia for secretions, salivation, freezing, reading difficulties, ocular-motor function, and
D E C L I N E
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TABLE 2. Means and SD for scores at the first, second, and third visits, 1-year worsening scores, and their 95% CIs
Time elapsed from first visit (years) S&E ADL UPDRS Mental, Behavior and Mood ADL Motor Total UPDRS Dysphagia UPDRS Salivation UPDRS Swallowing UPDRS Freezing UPDRS Falls unrelated to freezing UPDRS Motor: Postural stability Reading PSP-RS History Mentation Bulbar Ocular Limb Gait Total PSP-RS Ocular-Motor Function
PSP-RS Falls PSP-RS Gait Postural stability PSP-RS Dysphagia While Eating MMSE Total Score FAB (z-score) NPI Score Total Score Nighttime behavior disorders Neurovegetative Symptoms Appetite and Eating Disorders
Upward Downward Left Right
First Visit Mean 6 SD (n 5 27)
Second Visit Mean 6 SD (n 5 27)
Third Visit Mean 6 SD (n 5 5)
Worsening Score Estimated 6 SD
95% CI for Worsening Score
75.9 6 14.7
1.2 6 0.4 54.8 6 16.9@
2.0 6 0.3 36.7 6 5.8^
214.9 6 18.8
[–22.7, 27.0]
3.0 6 1.9 16.8 6 5.5 23.3 6 7.3 43.1 6 10.6 0.9 6 1.1 1.1 6 0.9 1.5 6 0.8 1.0 6 1.4 2.0 6 1.1 1.9 6 0.6 1.4 6 0.8
3.5 6 1.6# 23.8 6 6.6 31.5 6 12.4# 57.5 6 18.4# 1.3 6 0.9# 1.6 6 1.2 1.7 6 0.9# 1.9 6 1.4 2.5 6 1.1 2.0 6 1.1^ 2.1 6 1.01
3.0 6 0.7 26.4 6 9.8 48.8 6 13 78.2 6 22.2 1.6 6 0.5 1.6 6 0.9 1.8 6 0.8 2.0 6 1.8# 3.0 6 1.4 3.2 6 0.8 2.4 6 0.5
0.2 6 1.8 6.0 6 5.5 6.3 6 9.2 11.4 6 13.2 0.4 6 1.1 0.4 6 0.9 0.1 6 0.7 0.9 6 1.2 0.4 6 1.1 0.1 6 0.9 0.5 6 0.8
9.0 6 2.3 1.8 6 1.5 2.4 6 1.4 8.2 6 3.2 3.9 6 1.7 8.3 6 4.1 33.5 6 7.5 2.7 6 1.2 2.7 6 1.3 0.8 6 0.8 0.8 6 0.8 2.8 6 1.3 2.3 6 1.0 1.1 6 0.7 27.9 6 1.6 23.6 6 3.1 8.8 6 8.8* 3 6 4* 2.5 6 3.4Ø
10.6 6 3.2 4.0 6 2.2 3.1 6 1.4 11.4 6 3.3# 5.2 6 1.7# 11.7 6 4.9# 44.9 6 12.2 3.7 6 0.8# 3.6 6 0.6# 1.4 6 1.0# 1.6 6 1.2# 3.4 6 0.9 2.5 6 1.4# 1.4 6 0.7# 25.5 6 2.6^ 24.9 6 4.0^ 9.4 6 7.4@ 2.6 6 4.2@ 2.4 6 3.8@
10.2 6 1.8 4.2 6 3.0 4.0 6 1.0 13.2 62.9 7.6 6 5.5 15.6 6 4.8 54.8 6 15.2 460 460 1.8 6 1.3 1.8 6 1.3 460 3.6 6 0.5 1.6 6 0.9 24.6 6 4.4 27.2 6 3.4 4.0 6 3.6^ 0 6 0^ 4.0 66.9^
1.5 6 3.3 1.9 6 2.2 0.6 6 1.4 2.8 6 1.7 1.1 6 1.5 2.6 6 3.2 9.1 6 9.4 0.7 6 0.9 0.7 6 1.1 0.6 6 0.6 0.7 6 0.7 0.5 6 1.3 0.1 6 1.2 0.2 6 0.6 22.1 6 1.7 21.1 6 3.7 1.5 6 6.6 20.1 6 3.9 0.2 6 2.4
[–0.5, 0.9] [4.0, 8.1] [2.8, 9.8] [6.4, 16.3] [0.0, 0.8] [0.1, 0.8] [–0.1, 0.4] [0.4, 1.3] [0.0, 0.9] [–0.2, 0.5] [0.1, 0.8] [0.2, 2.7] [1.0, 2.7] [0.1, 1.2] [2.1, 3.4] [0.6, 1.7] [1.3, 3.8] [5.6, 12.7] [0.4, 1.1] [0.3, 1.1] [0.4, 0.8] [0.4, 1.0] [0.1, 1.0] [–0.4, 0.6] [0.0, 0.5] [–2.8, 21.4] [–2.5, 0.4] [–1.3, 4.3] [–1.7, 1.6] [–0.9, 1.4]
The number of observations at first and second visits was 27 and at the third visit was 5, unless otherwise identified by the following: # 5 1 missing; ^ 5 2 missing; *3 missing; 15 missing; @ 5 6 missing; and Ø 5 7 missing. On the UPDRS, PSP-RS, and NPI, positive change scores indicate worsening. On the S&E, MMSE, and FAB, negative scores indicate worsening.
falls were significantly larger than zero. The rate of progression of postural stability was not significantly different from zero. Table 3 shows the significant associations between progression rates and baseline variables as well as between the various worsening progression-rate variables. For example, the UPDRSADL progression rate was positively correlated with the progression of falls and with the baseline PSP-RS ocular motor score.
Sample-Size Estimation Table 4 shows sample sizes required for a two-arm 1-year follow-up therapeutic trial to detect 25% and 50% improvements, respectively, with a power at 80% and a significance level at 5%, assuming the same SD for both groups. The SD and amount of improvement for each variable were assumed to be known and obtained from Table 2. The sample size in Table 4
reflects the required sample size per group before adjusting for expected dropout. If we apply the typical 20% adjustment, then the sample size for PSP-RS ocular-motor subitems would be 32 (i.e., 25/0.8 5 32) per group for a 50% reduction of the progression rate. In PSP, however, the dropout rate is likely to be higher. If one assumes a drop-out rate of 30%, the required sample size would be 36 (i.e., 25/0.7 5 36) per group.
Discussion This longitudinal prospective study of 27 PSP patients showed a significant yearly decline in motor (total and subtotal scores of the PSP-RS and UPDRS motor and total scores), cognitive (MMSE), and ADL functions (UPDRS ADL and S&E scores). Previous studies have mostly focused on total scale scores, but we found that the decline was not only significant in
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TABLE 3. Significant associations between progression rates and baseline variables Worsening Score
S&E ADL
UPDRS Total ADL Score UPDRS Total Motor Score
UPDRS Total Score
PSP-RS Total History Score PSP-RS Total Bulbar Score PSP-RS Total Ocular Score PSP-RS Total Gait Score
PSP-RS Total Score
PSP-RS Dysphagia for secretions PSP-RS Dysphagia While Eating PSP-RS Voluntary Downward Saccades
PSP-RS Voluntary Left Saccades PSP-RS Falls UPDRS Falls
Worsening Score/Baseline
Correlation Coefficient
Adjusted P Value
PSP-RS Postural Instability PSP-RS Total Gait FAB z-score UPDRS Falls Baseline PSP-RS Total Ocular Score UPDRS Falls Total UPDRS Score Baseline NPI Neurovegetative SymptomsAppetite and Eating Disorders UPDRS Postural Instability UPDRS Total Mentation, Behavior, Mood Score UPDRS Total Motor Score PSP-RS Total Score PSP-RS Falls PSP-RS Postural Instability PSP-RS Dysphagia Baseline PSP-RS Total Bulbar Score PSP-RS Voluntary Downward Saccades UPDRS Falls UPDRS Postural Instability PSP-RS Postural Instability S&E UPDRS Postural Instability PSP-RS Postural Instability UPDRS Total Score PSP-RS Total Gait PSP-RS Total Bulbar Baseline PSP-RS Dysphagia for Secretions UPDRS Swallowing PSP-RS Voluntary Upward Saccades PSP-RS Total Ocular Baseline PSP-RS Voluntary Downward Saccades PSP-RS Voluntary Right Saccades Baseline PSP-RS Total History PSP-RS Total History Baseline PSP-RS Falls UPDRS Total ADL PSP-RS Total Gait Baseline UPDRS Falls Baseline PSP-RS Total Ocular
20.781 20.770 0.707 0.706 0.625 0.650 0.863 20.732
0.0012 0.0019 0.0229 0.0026 0.0331 0.0298
