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The current study sought to describe the functional profiles of patients with early-stage progressive supranuclear palsy (PSP) in a large prospective, multisite study.
Using data from 202 individuals meeting criteria for clinically definite or probable PSP, 3 functional scales were examined. Functional scores were then compared to measures of motor, cognition, and psychiatric symptoms.
Functional disability was high in early-stage PSP, with 100% of patients having less than perfect scores on all functional scales. Whereas functional scores tended not to be related to cognition or psychiatric symptoms, they were strongly related to motoric ratings.
Both clinically and in research settings, the definition of functional intactness/impairment has important implications. Future studies should examine if functional impairment is this high in PSP or if new scales of functional abilities need to be developed for this condition.
Progressive supranuclear palsy (PSP) is a rare neurologic disorder primarily presenting with motor disturbances (e.g., postural instability, parkinsonism, slowing of vertical saccades).1 As in other neurodegenerative conditions, patients with PSP also display difficulties with cognition,2 psychiatric functioning,3 and quality of life.4 Functional disability observed in these patients is less clear, however.
Functionally, impairments can occur with basic (e.g., bathing, grooming, dressing) and instrumental (e.g., working, driving, managing medications) activities of daily living (ADL). The presence and level of functional impairment has clinical and research implications. Clinically, the presence or absence of functional impairment may dictate a diagnosis of dementia or mild cognitive impairment, respectively.5 ADL impairment may indicate the amount of rehabilitative services or placement options for patients. Outcome measures in clinical trials are often tied to functional measures, as the Food and Drug Administration preferentially ascribes to them.6
Little has been published on functional abilities in PSP. In a small sample, 75% were functionally independent within the first few years of the disease.7 Conversely, in a large international cohort, the average patient with PSP was partially dependent, needing assistance with half of his or her daily chores.8
Given this variability in functional abilities in PSP and the importance of this topic, the current study examined functional profiles of patients with early-stage PSP in a large prospective, multisite study. It was expected that functional disability would be high, even in this early phase cohort, and that functional disability would correlate with motor, cognitive, and psychiatric symptoms.
Study participants included 202 patients with PSP recruited at 13 sites (Baylor University, University of Colorado, Cornell University, Case Western Reserve, Emory University, Kansas University, University of Louisville, University of Alabama Birmingham, University of California at Los Angeles, University of Kansas, Toronto Hospital, Mayo Clinic Jacksonville, and University of Washington). All patients needed to meet the National Institute of Neurological Disorders and Stroke and Society for PSP, Inc.9 criteria for clinically probable or definite PSP. Probable PSP is defined in these criteria as gradually progressive, onset ≥40 years of age, vertical supranuclear palsy and postural instability with falls within the first year of symptom onset, and an absence of other explanatory conditions. Definite PSP is defined as clinically relevant signs of PSP and histopathologic evidence typical of this disease. Participants in the current study also needed a Mini-Mental State Examination score ≥24 to be included. Patients were excluded if they had other CNS disorders (e.g., Parkinson disease, multiple system atrophy, corticobasal degeneration) or were unable to provide informed consent.
After informed consent, patients were evaluated by a clinical team consisting of a movement disorders specialist and trained research assistant to confirm the PSP diagnosis. This evaluation included a neurologic history and examination, completion of validated PSP instruments (Progressive Supranuclear Palsy Rating Scale [PSP-RS]),10 and the Unified Parkinson’s Disease Rating Scale (UPDRS).11 Videotaping of motor functioning was also collected to monitor consistency among sites. Finally, a baseline neuropsychological evaluation was completed by medical personnel who had received training on the battery from a neuropsychologist.
All procedures were approved by local institutional review boards at all ENGENE-PSP sites prior to commencing study procedures. All study participants provided written informed consent prior to data collection.
The UPDRS11 was originally developed for use in evaluating impairment in Parkinson disease, but it has also been shown to be a valid and reliable measure for PSP. The UPDRS contains 3 sections, but only the ADL and motor functioning sections were used in these analyses. The ADL section contains 13 items that inquire about activities such as swallowing, handwriting, using utensils, dressing, and walking. The motor section contains 27 items that rate the patient's motor signs (e.g., resting tremor, rigidity, finger tapping, posture, gait). Both of these sections are rated on a 0–4 Likert scale (0 = normal/sign absent; 4 = severe disability/sign), with higher scores indicative of greater impairment.
The Schwab & England Activities of Daily Living Scale (SE-ADL)12 is used to evaluate the independence of an individual. Scores are grouped in units of 10, with 100 being indicative of a patient who is completely independent (i.e., able to do all chores without slowness, difficulty, or impairment) and 0 being indicative of a patient who is vegetative. The SE-ADL comprises part VI of the UPDRS.
The PSP-RS10 assesses the level of impairment in patients with PSP. Impairment is assessed across 6 categories: health history, mentation, bulbar function, eye and lid movement, limb movement, and trunk movement, with each item being rated on a 0–4 Likert scale (0 = no sign/symptom; 4 = severe sign/symptom). For the current analyses, only items that relate to daily activities were examined.
The Dementia Rating Scale–2 (DRS-2)13 is a measure of general cognitive functioning that is widely used in geriatric clinical and research assessments. It assesses attention, construction, memory, and executive functioning, and it yields an age-, education-, and race-corrected total score.14,15 For this score, higher values indicate better cognitive functioning.
The Neuropsychiatric Inventory (NPI)16 is used to assess both the frequency and severity of behavioral abnormalities across 10 domains: delusions, hallucinations, agitation, depression, anxiety, euphoria, apathy, disinhibition, irritability, and aberrant motor behavior. Caregivers are asked to rate affected behaviors on a 1–4 scale for frequency (1 occasionally, 2 often, 3 frequently, and 4 very frequently) and a 1–3 scale for severity (1 mild, 2 moderate, 3 severe). Each domain is calculated by multiplying frequency and severity. NPI total score is the sum of the 10 domains.
To more closely examine the functional abilities and disabilities associated with PSP, means, SDs, and cumulative frequencies were observed for the total score and item scores for the UPDRS-ADL section, SE-ADL, and items from PSP-RS corresponding to ADL. To examine the clinical correlates of function in PSP, correlations were computed between each ADL measure total score and UPDRS motor score, DRS-2 total score, and NPI total score. Finally, correlations were computed between each of the 3 ADL measures. Given the number of statistical comparisons, a p value of 0.01 was used.
There were 113 men and 89 women in this sample, with a mean age of 68.0 years (SD 6.6, range 53–87), mean education of 15.0 years (SD 3.5, range 8–20), and mean duration of symptoms of 3.8 years (SD 1.6, range 0.6–10.0). For the entire group, motor signs were evident (UPDRS motor: mean 30.5, SD 12.8, range 8–66), cognition tended to be impaired (DRS-2 total: mean 124.5, SD 11.9, range 88–144), and most demonstrated psychiatric symptoms (NPI total: mean 18.8, SD = 9.2, range 1–50). The mean UPDRS-ADL score for the cohort was 18.9 (SD 7.3, range 4–38), their mean SE-ADL score was 61.3 (SD 21.3, range 20–100), and their mean PSP-RS score was 6.4 (SD 2.5, range 1–13). Their frequency distributions are presented in the figure.
All ADL measures were significantly related to motor scores on the UPDRS (UPDRS-ADL: r = −0.62, p < 0.001; SE-ADL: r = −0.66, p < 0.001; PSP-RS: r = 0.47, p < 0.001). Only 1 of the 3 ADL measures was significantly correlated with cognition, as measured by the DRS-2 total score (SE-ADL: r = 0.20, p = 0.01). Overall psychiatric symptoms, as assessed by the NPI total score, were not associated with any of the ADL measures. Secondary analysis of the NPI subscales revealed only one notable finding: the disinhibition subscale was related to the UPDRS ADL (r = 0.20, p = 0.01) and the PSP-RS (r = 0.21, p = 0.008).
All ADL measures were also significantly related to each other (UPDRS-ADL and SE-ADL: r = −0.69, p < 0.001; UPDRS-ADL and PSP-RS: r = 0.73, p < 0.001; SE-ADL and PSP-RS: r = −0.57, p < 0.001).
Consistent with the a priori expectations of this study, functional impairment was high in this large cohort of patients with early-stage PSP. To our knowledge, there are no widely accepted cutoff scores on the 3 functional rating scales used in this study to denote “functional impairment.” However, if one assumes that any impairment is abnormal, then 100% of these 202 participants had less than perfect scores on all scales, suggesting at least some functional disability. The level of impairment was also not inconsequential for our average participant. For example, the mean score on the SE-ADL of 61.37 suggests “some dependency.” Similarly, a mean score of 18.92 on the UPDRS-ADL indicates at least “mild” or “slight” difficulties on every item of that scale. These results are consistent with those reported in another large-scale study of PSP.8
Given the triad of signs and symptoms of PSP, it is unclear what factors contribute to the “functional impairment” in this condition, but this led us to examine the clinical correlates of functional scores. Although impairments in ADLs are typically considered in the diagnosis of dementia, 2 of the 3 ADL measures were not related to cognition in this PSP cohort. And although scores on the third measure, SE-ADL, were significantly related to scores on the DRS-2 total, the amount of shared variance was very small (~4%), suggesting that other factors may be more involved in functional abilities. Psychiatric symptoms, including depression, anxiety, and apathy measured with the NPI, were also not significantly associated with functional abilities on any of the rating scales. Conversely, all ADL measures were significantly related to motor scores, assessed by the UPDRS.17 This seems to suggest that the functional disability experienced by patients with PSP is primarily due to their physical disability, rather than cognitive or psychiatric conditions. Impaired ADLs within various movement disorders have not always found consistent clinical correlates. For example, Holroyd et al.17 observed that ADL impairment in Parkinson disease was more strongly correlated with depression than with motor functioning. Paulsen et al.6 found ADL decline to be related to cognition, depression, and motor functioning in prodromal Huntington disease. The ties between these various signs and symptoms likely depend on the particular disorder, the severity of the illness, and the measures being used in a given study.
Although these findings may seem obvious to clinicians who have evaluated patients with PSP, they have important diagnostic implications. We have previously found that approximately three-quarters of the current sample display cognitive impairment on the various screening measures. If functional impairment is also observed (as it was in 100% of these patients), then the vast majority of this early-stage sample with a Mini-Mental State Examination score of ≥24 could be diagnosed with dementia. The diagnosis of comorbid dementia in most patients with PSP is likely to have treatment implications as well (e.g., medication options, referrals for supportive services). Finally, as clinical trials are being developed for patients with PSP,18 these results raise questions about the study design and outcome measures of future trials. For example, should functional intactness be required as an inclusion criterion in these trials? Can disease-modifying trials be conducted in conditions where most patients already have dementia? Are any current functional scales sufficiently sensitive to detect changes in functional abilities in this population?
Although our initial supposition was that any functional impairment was abnormal, it might be more appropriate to consider a lower threshold for functional impairment. However, it is unclear what lower threshold would be appropriate. If one used the mean score on any of the rating scales, then approximately half of our sample would be functionally impaired. Would one SD above (or below) the mean be more appropriate? Before choosing a cutoff, one must appreciate the level of ADLs assessed with the current rating scales. Items assessed in current scales are very basic, including swallowing, cutting food, turning in bed, and walking. With this in mind, our original supposition of any impairment is enough may be fitting. However, current scales give us no information about higher-level ADLs, like driving, work, or managing finances or medications. Clearly, there is a need for a more accurate assessment of daily functioning in these patients.
Despite the findings presented in the current study, some cautions should be mentioned. First, like other multisite studies of rare disorders, the current sample may not completely represent the population from which is was drawn. The current participants agreed to several hours of testing, they needed to have a Mini-Mental State Examination score ≥24, they needed to be able to provide informed consent, and they could not have other CNS disorders. These inclusion criteria likely yield a selected group of patients with PSP, and these results might not generalize to all patients with PSP. Second, the functional rating scales used in the current study might be standard in the field, but they are not particularly comprehensive of all daily activities. Whereas they focus on basic ADL, they provide little direct information about higher ADL. Third, the currently used functional scales utilize clinician ratings based on input from the patient and an informant. Performance-based measures (e.g., University of California San Diego Performance-Based Skills Assessment used in schizophrenia) may have led to very different results. Finally, we were unable to subtype these patients (e.g., Richardson syndrome vs PSP-parkinsonism), and it is possible that differences exist between these subtypes on ADL performance. Regardless of these limitations, the current study has identified that functional impairment in PSP is pervasive and largely related to motoric dysfunction. Without a finer understanding of functional abilities in these patients, clinical care and research is likely to suffer.
The authors thank the patients who participated in this study and their families and the following contributors for their support: coordinators, motor raters, cognitive raters: Richard Dubinsky, MD, MPH (University of Kansas); David Shprecher, DO (University of Utah); Claire Henchcliffe, MD, DPhil (Cornell University); Benzi Kluger, MD (University of Colorado); Ryan Uitti, MD (Mayo Clinic, Jacksonville).
The Investigators and Coordinators of the ENGENE-PSP Study Group are listed on the Neurology® Web site at www.neurology.org.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Supplemental data at www.neurology.org
Kevin Duff, PhD: design or conceptualization of the study, analysis or interpretation of the data, drafting or revising the manuscript. Adam Gerstenecker, MS: design or conceptualization of the study, analysis or interpretation of the data, drafting or revising the manuscript. Irene Litvan, MD: design or conceptualization of the study, analysis or interpretation of the data, drafting or revising the manuscript.
Supported by a NIH grant (5R01AG024040-04).
The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.