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Functional Decline in Parkinson Disease
Joseph Jankovic, MD;
Asha S. Kapadia, PhD
Arch Neurol. 2001;58:1611-1615.
ABSTRACT
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Objectives To determine the overall rate of functional decline and to assess the
progression of different signs of Parkinson disease (PD).
Patients and Methods Patients with clinically diagnosed PD followed up for at least 3 years
were included in this study. Demographic and clinical data (including the
Unified Parkinson's Disease Rating Scale [UPDRS]) were analyzed by the multivariate
unbalanced repeated-measurements design using the mixed-effects model to study
the association between different symptoms and various demographic variables.
Regression models helped estimate the rates of progression of the disease
in relationship to the various components of the UPDRS. Patients were categorized
as having tremor-dominant or postural instability–gait difficulty–dominant
PD and the 2 categories were compared for progression of their total UPDRS
scores.
Design A multivariate mixed-effects model was used to study the relationship
between the different symptoms and various demographic variables. Nonparametric
statistical tests were used to compare the progression of symptoms in the
"on" (good function) state and the "off" (poor function) state groups for
2 age-at-onset categories ( 57 and >57 years).
Results Data from 1731 visits on 297 patients (181 men) followed up for an average
of 6.36 years (range, 3-17 years) were analyzed. The annual rate of decline
in the total UPDRS scores was 1.34 when assessed during the on state and 1.58
when assessed during the off state. Patients with an older age at onset had
more rapid progression of PD than those with a younger age at onset. Furthermore,
the older-onset group had statistically significantly more progression in
mentation, freezing, and parts I (mentation) and II (activities of daily living)
UPDRS subscores. Handwriting was the only component of the UPDRS score that
did not notably deteriorate during the observation period. Regression analysis
of 108 patients whose symptoms were rated during their off state showed a
faster rate of cognitive decline as age at onset increased. The slopes (ie,
the annual rates of decline) of progression in the UPDRS scores, when adjusted
for age at the initial visit, were steeper for the postural instability–gait
difficulty–dominant group compared with the tremor-dominant group.
Conclusion Based on longitudinal follow-up data, our findings provide evidence
for a variable course of progression of the different PD symptoms, thus implying
different biochemical or degenerative mechanisms for the various clinical
features associated with PD.
INTRODUCTION
PROGRESSIVE decline in motor function is the expected natural course
of Parkinson disease (PD). There is, however, little or no information on
what demographic or clinical features determine or influence the rate of progression
of the disease and of the different symptoms. Although some studies have attempted
to address this important issue,1, 2, 3, 4, 5, 6, 7, 8, 9
most are based on a cross-sectional design or only a short follow-up. Furthermore,
while the clinical heterogeneity of PD is well recognized, to our knowledge
the long-term prognosis of the different clinical subtypes has not been studied
prospectively.
Besides the clinical variability between patients, the different parkinsonian
features manifested by individual patients seem to progress at different rates,
suggesting a variable involvement of the dopaminergic system and possibly
other pathways. Furthermore, it is well recognized that not all patients with
PD or with signs of PD respond the same way to levodopa treatment.2, 10 The primary objectives of this study
are to determine the overall rate of functional decline and to assess the
progression of different signs over time in patients with PD who are receiving
treatment.
PATIENTS AND METHODS
DATA COLLECTION
Demographic (ie, sex, age at onset, and current age) and clinical data
on 297 consecutive patients diagnosed by 1 of us (J.J.) as having typical
PD and who were followed up for at least 3 years at Baylor College of Medicine
Parkinson Disease Center, Houston, Tex, between 1985 and 2001 were entered
into the database. All patients were examined at their initial and subsequent
visits for any evidence of atypical features, such as early onset of cognitive
decline, postural instability, autonomic dysfunction, or poor response to
levodopa treatment. Their condition was also rated on the Unified Parkinson's
Disease Rating Scale (UPDRS).11 Only patients
in whom the diagnosis of PD was maintained during the follow-up period were
included in this study; those with atypical parkinsonism suggestive of progressive
supranuclear palsy, multiple system atrophy, or other parkinsonian disorders
were excluded. In patients treated with levodopa, we specified whether the
UPDRS data were obtained when the patients were examined during the "on" (good
function) or "off"(poor function) state. The UPDRS rating was categorized
as on state when the patients reported that their improvement after the last
dose of levodopa treatment was optimal (even though it may have been accompanied
by dyskinesias), whereas the off-state scores reflected their state when the
levodopa effects from the previous dose completely or almost completely wore
off. For practical and ethical purposes, the patients were not instructed
to come to the clinic in their off state after an overnight abstinence from
levodopa treatment. During the course of their follow-up, the patients were
treated with a variety of antiparkinsonian medications besides levodopa, including
selegeline hydrochloride and dopamine agonists. An independent audit was performed
on 50% of randomly selected medical records to ensure the accuracy of the
entered data, as verified against the original records.
STATISTICAL ANALYSIS
The UPDRS scores for each patient visit were first categorized by the
patient's on- or off-state status. Because the number of patient visits in
the 2 groups varied from patient to patient, the usual statistical techniques
for analysis of repeated measurements was not applicable to this data set.
A multivariate unbalanced repeated-measurements design12
was used to study the relationship between the different symptoms (bradykinesia,
falling, walking, freezing, postural stability, tremor, gait, speech, handwriting,
sensory, and mentation) and age at onset, sex, duration of symptoms, years
of observation, and handedness in the on- and off-state groups. An SAS statistical
program (SAS, Cary, NC) was used for the analysis.13
Disease progression was defined as the difference between the baseline
and the last score for the various components of the UPDRS scores. Multivariate
regression models were developed for both the on and off states to study the
association of the progression in the total UPDRS scores for parts I through
III (ie, mentation, activities of daily living, and motor function, respectively)
and the combined score for all 3 parts after adjusting for years of observation.
The mean tremor score was defined as the mean of the sum of the baseline tremor
(UPDRS part II) and tremor scores (UPDRS part III) for face, right and left
hand, right and left foot, and right and left hand action tremor. The mean
postural instability–gait difficulty (PIGD) score was defined as the
sum of an individual's baseline falling, freezing, walking, gait, and postural
stability scores divided by 5. Patients were categorized as having tremor-dominant
PD if the ratio of the mean tremor score to the mean PIGD score was 1.50 or
higher and as PIGD dominant if the ratio was 1.00 or lower, similar to previously
published method.6 Using the 2-sample t test,14 the 2 PD-dominant
groups (tremor and PIGD) were compared for progression of their total UPDRS
scores.
Mann-Whitney nonparametric statistical tests14
were used to compare the progression of symptoms in the on- and the off-state
groups for 2 age-at-onset categories (ie, 57 and >57 years, based on the
median age at onset of 57 years) as well as comparing the progression in mentation
when individuals at baseline were categorized as below and above the baseline
median mentation score.
RESULTS
The 297 patients (181 men) generated a total of 2717 of on- and off-state
scores in 1731 visits (mean, 5.80 visits per patient; range, 2-24 visits per
patient). The average follow-up was 6.36 years (range, 3-17 years). The average
age at onset of symptoms was 55.10 years (range, 16-82 years; median, 57 years)
and the average duration of symptoms at the time of the initial visit was
6.50 years (range, 0.05-50 years).
In the multivariate, unbalanced, repeated-measurements design model,
no statistically significant (P>.05) effect of any
of the independent factors on the (various) dependent variables was observed.
This was true both for the on- and the off-state data sets. The progression
of impairment assessed during the on state, determined by the differences
between the baseline and the last visit scores for the total UPDRS scores
averaged over all of the patients and divided by the average number of years
of follow-up (6.36 years), resulted in an average decline of 1.34 during the
on state and 1.58 during the off state per patient per year of observation.
The corresponding projected declines predicted from the regression model were
1.43 and 2.97, respectively. Part I UPDRS scores, however, did not decline
as rapidly as the other parts of the UPDRS (Figure 1). It was further observed that totals for the part I and
II UPDRS scores (n = 294) positively correlated (P<.01)
with age at onset, implying more rapid progression of disease in individuals
whose symptoms began at an older age. Except for handwriting, all components
of UPDRS parts I and II worsened during the period of observation (Table 1).
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Figure 1. The slow progression in United
Parkinson's Disease Rating Scale part I (mentation), part II (activities of
daily living), and part III (motor function) scores compared with the total
United Parkinson's Disease Rating Scale score in the "off" (poor function)
(A) (n = 108 patients) and "on" (good function) (B) (n = 294 patients) states
supports the notion that Parkinson disease predominantly affects the motor
system. Slope indicates the annual rate of decline of function.
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Progression in UPDRS "On"-State Scores for 294 Patients*
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MEN VS WOMEN?
When on-state patients with young age at onset (57 years, n = 159
patients) were compared with those whose symptoms began after 57 years (n
= 133), the older-onset group had significantly (P<.05)
more progression in mentation and freezing, and lower UPDRS part I and II
subscores. The projected relationship of the total UPDRS scores for the 2
age-at-onset categories with years of observation are plotted in Figure 2. The progression of total mentation
scores in patients with baseline mentation scores above the median (n = 126
patients) was significantly greater (P<.05) than
in those with baseline mentation scores below the median (n = 171 patients).
The average projected decline in the mentation score for the 2 groups was
0.647 and 0.102, respectively.
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Figure 2. The progression, measured by the
total United Parkinson's Disease Rating Scale "on" (good function) scores
(n = 133 patients), was more rapid in patients with an age at onset after
57 years compared with the young-onset age group. Slope indicates the annual
rate of decline of function.
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When the tremor-dominant group (n = 77 patients) in the on-state data
set was compared with the PIGD-dominant group (n = 149 patients), the only
comparison that was statistically significant was the one between total UPDRS
part II subscores; the unadjusted means of the tremor-dominant and PIGD-dominant
groups were 5.38 and 2.76, respectively (P<.05),
for this set of subscores. However, when the slopes (ie, annual rate of decline)
of progression per year of observation after adjustment for age at the initial
visit were compared between the 2 groups, it was observed that the PIGD-dominant
group had a higher projected slope than the tremor-dominant group in all the
cases (UPDRS parts I through III and the total UPDRS scores). Figure 3 shows the progression of total UPDRS on-state scores per
year of observation for the 2 groups.
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Figure 3. The more rapid progression in
149 patients with the postural instability–gait difficulty (PIGD) form
of Parkinson disease (PD) compared with 77 patients with tremor-dominant PD
is consistent with previous reports (see "Comment" section of the text). All
values were adjusted for age at the intitial visit. Slope indicates the annual
rate of decline of function.
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In the multivariate regression models when the progression (in UPDRS
parts I through III and the total UPDRS on-state scores, respectively) was
analyzed for age at onset, type of PD (tremor dominant or PIGD dominant),
and sex, male patients progressed at a significantly (P<.05) higher rate than female patients in the UPDRS parts I and
II subscores (slopes, 0.962 and 2.65, respectively). It was also observed
that the UPDRS part II subscores were significantly associated (P<.05) with age at onset and type of PD (the corresponding rates
of progression were 0.135 and 2.64, respectively).
COMMENT
This study of 297 patients, followed up prospectively for an average
of 6.30 years, constitutes the largest longitudinally followed up cohort of
patients with PD. The purpose of the study is not to determine the natural
course of untreated disease, which would be ethically unacceptable, but to
define factors that may influence the progression of various symptoms in treated
PD. We found the annual rate (slope) of decline in the total UPDRS scores
to be 1.34 in the on state and 1.58 in the off state. The corresponding projected
annual rates of decline based on the regression model were 1.43 and 2.97,
respectively. These results are similar to the 1.5-point annual decline, based
on longitudinal assessments using the motor function (part III) portion of
the UPDRS reported by Louis et al9 in a community-based
study of 237 patients with PD followed up prospectively for a mean of 3.30
years. Several studies have suggested that the rate of progression may not
be linear and that the disease may progress more rapidly initially and the
rate of deterioration slows in more advanced stages of the disease. This is
supported by our findings in moderately advanced cases of PD requiring levodopa
treatment compared with patients in early stages of the disease such as those
enrolled in the DATATOP study.15 In that study
of early, previously untreated patients, the rate of annual decline in the
total UPDRS score was 14.02 ± 12.32 (mean ± SD) in the placebo-treated
group. In contrast, in a group of 238 patients treated with levodopa, bromocriptine
mesylate, or both in whom progression was estimated based on a retrospectively
determined duration of the symptoms, the annual rate of decline in bradykinesia
score was 3.5% during the first year but was estimated to be only 1.5% in
the 10th year.4 Furthermore, Jennings et al16 found, based on sequential 2ß-carboxymethoxy-3ß-(4[123I]iodopheynyl)tropane and single-photon emission computed tomographic
imaging at intervals ranging from 9 to 24 months that annual rate of loss
of striatal {2ß-carboxymethoxy-3ß-(4[123I]iodopheynyl)tropane}
uptake to be 7.14% in subjects having a diagnosis of PD for fewer than 2 years
compared with a 3.71% rate in those having a diagnosis of PD for longer than
4.5 years. In a more recent study using fludeoxyglucose F18–fluorodopa
F6 positron emission tomography, Nurmi et al17
showed a 10.3% ± 4.8% decline in the uptake in the putamen over a 5-year
period. Finally, based on clinicopathological correlation, Fearnley and Lees18 suggested that there is a 30% age-related nigral
cell loss at disease onset, again indicating rapid decline in nigral dopaminegic
cells in the early stages of the disease.
Besides the variable rate of progression during the natural course of
the disease, there is evidence that individual parkinsonian symptoms have
a variable rate of progression. Louis et al9
found that in contrast to bradykinesia, rigidity, and gait and balance, all
of which progressed at the same rate, tremor was independent of these cardinal
signs. This is also consistent with the results of an earlier and a much smaller
study involving only 25 patients, followed up prospectively for at least 10
years after initiation of levodopa treatment.2
In that study, tremor, rigidity, and micrographia (similar to our study) remained
improved, whereas speech, postural reflexes, and gait difficulty continued
to deteriorate despite levodopa treatment. We also found that, in contrast
to other symptoms, handwriting had not significantly deteriorated during the
observation period (Table 1).
At least 2 different forms of PD have been proposed: one characterized
by PIGD and another dominated by tremor.6, 19
The tremor subtype of PD is associated with preserved mental status, earlier
age at onset, and slower progression of the disease compared with the PIGD
subtype, which is characterized by more severe bradykinesia, cognitive impairment,
and a more rapidly progressive course. Furthermore, the PIGD-dominant type
of PD had a higher risk of reaching an end point, the degree of disability
necessitating levodopa treatment, in the DATATOP study.7
The association between axial (PIGD) impairment and incident dementia has
been demonstrated also by other studies.5, 19
Our longitudinal follow-up study provides support for the hypothesis that,
based on total UPDRS scores, the PIGD group has a less favorable prognosis,
showing a steeper slope of progression than the tremor-dominant group (Figure 3).
The variable rate of progression of different types of PD suggests different
pathological and biochemical mechanisms and possibly different causes, supporting
the notion of Parkinson diseases rather than a single disease entity. This
is supported by pathological and genetic studies indicating different mechanisms
for phenotypically similar disorders. In one study of patients having clinically
diagnosed PD, only 27% of patients with the PIGD form of idiopathic parkinsonism
had Lewy bodies at autopsy.20 Furthermore,
even within PD, the variable progression of individual signs suggests different
pathological and biochemical mechanisms. For example, Hirsch et al21 have demonstrated that patients with PD and prominent
tremor have a degeneration of a subgroup of midbrain (A8) neurons, whereas
this area is spared in patients with PD without tremor. Using fludeoxyglucose
F 18–fluorodopa F 6 positron emission tomography, Vingerhoets et al22 demonstrated that bradykinesia is the parkinsonian
sign that correlates best with nigrostriatal deficiency. In contrast, patients
with the tremor-dominant PD have increased metabolic activity in the pons,
thalamus, and motor association cortices.23
These findings support the hypothesis that differential damage of subpopulations
of neuronal systems is responsible for the diversity of phenotypes seen in
PD and other parkinsonian disorders. Further clinicopathological-biochemical,
and eventually genetic, studies will be required to clarify the mechanisms
underlying the observed clinical heterogeneity and to develop highly predictive
diagnostic criteria.24
The course of PD may be influenced not only by the clinical presentation
of the disease, but also by age at onset and various external factors such
as stress,25 pregnancy,26
and anti-PD therapy.27 Several studies, for
example, have demonstrated that patients with young-onset PD progress at a
slower rate than the late-onset patients, but the patients with young-onset
PD are more likely to develop levodopa-induced dyskinesias early in the course
of treatment.28, 29, 30, 31
Furthermore, the late-onset subtype is characterized by rapidly progressive
motor and cognitive disability.5, 32
In this study we confirmed that patients 57 years or older with late onset
of symptoms had a more rapid progression of disease than those whose symptoms
began before the age of 57 years. We also showed that men and older patients
progress at a more rapid rate than female patients and patients with young-onset
PD. Furthermore, our and other studies have shown that patients with predominantly
axial involvement (such as those with the PIGD-dominant type of PD) are more
likely to manifest cognitive decline compared with the more typical form of
PD.5 This subset of patients may have additional
nondopaminergic degeneration, thus explaining the poor response to treatment
with levodopa and dopamine agonists.33 Indeed,
our findings challenge the traditional view that the symptoms of PD are solely
due to nigrostriatal dopamine deficiency. There is growing evidence that local
dendritic release of dopamine by neurons in the substantia nigra pars compacta
and ventral tegmental influences basal ganglia functions and thus may affect
the clinical expression and prognosis.34 Furthermore,
norepinephrine, serotonin, and other nondopaminergic systems may play an important
role in the production of certain PD symptoms and in the natural course of
the disease. Finally, as a result of growing appreciation for genetic and
other causes, we no longer view PD as a single disease entity but a group
of diseases with different pathogenic mechanisms that may variably influence
the natural course of the disease.
The results of our study must be interpreted cautiously because the
patients were in different stages of their disease at the time of their initial
visit, they were followed up for different periods, and they were treated
with levodopa and other antiparkinsonian drugs at different dosages and for
a variable time. There is no evidence, however, that any of the currently
used drugs are neuroprotective or affect the natural progression of the disease.
Although we provide UPDRS data during the on and off states, this was based
on clinical judgment at the time of the visit and patients were not necessarily
at the peak of optimal response (on state) or in their true off state (at
least 12 hours after the last dose of levodopa treatment). Because we were
interested in the natural course of treated PD, prolonged withdrawal of levodopa
treatment (drug holiday) was not justified nor would it be safe or ethical.
Furthermore, as this was not a clinicopathological study, some of our patients
having the clinical diagnosis of PD could have had an alternative diagnosis
if examined at autopsy. Despite these limitations, the findings from this
longitudinal study provide evidence that the various symptoms associated with
PD do not progress at the same rate and that they may be mediated through
different pathogenic mechanisms. The findings from this study may be useful
in designing future clinical trials of therapeutic interventions affecting
the natural course of the disease.
AUTHOR INFORMATION
Accepted for publication July 5, 2001.
We thank the National Parkinson Foundation, Miami, Fla, and Amgen Inc,
Thousand Oaks, Calif, for their financial support.
We also express our appreciation to Charles F. Contant, Jr, PhD, Kevin
Vuong, MS, Christine Hunter, RN, Cathy Jankovic, Fay Goston, Le Ben-Arie,
and Kim Chen, BS, for their technical assistance.
From the Department of Neurology, Baylor College of Medicine (Dr Jankovic),
and the School of Public Health, University of Texas (Dr Kapadia), Houston.
Corresponding author: Joseph Jankovic, MD, Department of Neurology,
6550 Fannin, No. 1801, Houston, TX 77030 (e-mail: josephj{at}bcm.tmc.edu).
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Contribution of Aging to the Severity of Different Motor Signs in Parkinson Disease
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Imaging the dopamine system to assess disease-modifying drugs: Studies comparing dopamine agonists and levodopa
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Levodopa strengths and weaknesses
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