Neurosci Bull February 1, 2012, 28(1): 39–48. http://www.neurosci.cn
Corresponding author: Ruiping Xia
Tel: +1402-280-5946; Fax: +1402-280-5692
Article ID: 1673-7067(2012)01-0039-10
Received date: 2011-10-06; Accepted date: 2011-11-30
Progression of motor symptoms in Parkinson’s disease
Ruiping Xia1, Zhi-Hong Mao2
1Department of Physical Therapy, School of Pharmacy and Health Professions, Creighton University, Omaha, Nebraska,
2Department of Electrical and Computer Engineering and Department of Bioengineering, University of Pittsburgh, Pitts-
burgh, Pennsylvania, USA
© Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2012
Abstract: Parkinson’s disease (PD) is a chronic progressive neurodegenerative disease that is clinically manifested by a
triad of cardinal motor symptoms - rigidity, bradykinesia and tremor - due to loss of dopaminergic neurons. The motor
symptoms of PD become progressively worse as the disease advances. PD is also a heterogeneous disease since rigidity and
bradykinesia are the major complaints in some patients whereas tremor is predominant in others. In recent years, many
studies have investigated the progression of the hallmark symptoms over time, and the cardinal motor symptoms have dif-
ferent rates of progression, with the disease usually progressing faster in patients with rigidity and bradykinesia than in
those with predominant tremor. The current treatment regime of dopamine-replacement therapy improves motor symptoms
and alleviates disability. Increasing the dosage of dopaminergic medication is commonly used to combat the worsening
symptoms. However, the drug-induced involuntary body movements and motor complications can significantly contribute
to overall disability. Further, none of the currently-available therapies can slow or halt the disease progression. Significant
research efforts have been directed towards developing neuroprotective or disease-modifying agents that are intended to
slow the progression. In this article, the most recent clinical studies investigating disease progression and current progress
on the development of disease-modifying drug trials are reviewed.
Keywords: Parkinson’s disease; progression; motor symptoms; disease modification; treatment
Parkinson’s disease (PD) is a chronic neurodegenera-
tive disease with a relentlessly progressive course[1,2]. It
is also the most common form of movement disorder and
the second most common neurodegenerative disorder, cur-
rently affecting an estimated five million people world-
wide. The incidence and prevalence of PD are expected
to increase exponentially as the population ages. Its patho-
logical hallmark is the loss of pigmented dopaminergic
neurons in the substantia nigra pars compacta, leading to
various motor symptoms such as bradykinesia, rigidity,
rest tremor, and postural instability at a later stage of the
disease[5,6]. These symptoms are frequently referred to as
cardinal motor symptoms, which become progressively
worse as the disease advances. Increasing the dose of do-
paminergic medication is a common approach against the
worsening symptoms. However, the benefits of higher doses
are offset by the side-effects, such as dyskinesia, motor
fluctuations, confusion, and hallucination. After 10–20
Neurosci Bull February 1, 2012, 28(1): 39–48
years of disease history, 40%-75% of patients with PD die,
and about 50% of those who survive require nursing-home
The clinical diagnosis of PD is based on a combina-
tion of cardinal motor symptoms: bradykinesia, rigidity,
and rest tremor. A positive response to dopamine-replace-
ment therapy may further confirm the initial diagnosis,
since a great majority of patients with PD exhibit a good
initial response to levodopa. In general, patients with
PD do not necessarily experience all the cardinal motor
features at diagnosis. Many clinical studies have indicated
that the distinctions among the cardinal motor symptoms
are significant although they share similarities and com-
mon origins. The rate and the type of symptom progres-
sion are heterogeneous across patients and through the
course of disease within the same patient. The heterogene-
ity among patients is reflected by two major sub-types:
akinetic-rigid and tremor-dominant[10-13]. Further, different
clinical phenotypes exhibit different prognoses with a faster
progression in patients with bradykinesia and rigidity and
a milder progression in those presenting with tremor-domi-
During the past 10–20 years, there has been an increas-
ing recognition of non-movement-related symptoms. Thus
far, our understanding of PD has been evolving from the
traditional pathologic concept of a disease entity of primar-
ily motor features to a more dynamic approach involving
multiple entities. There is generally a wide spectrum of
non-motor symptoms involving multiple pathologies and
entities, including but not limited to autonomic, gastroin-
testinal, neuropsychiatric, and sensory symptoms. Ac-
cumulating evidence shows that non-motor symptoms can
occur at any stages of the disease process, with some oc-
curring prior to the onset of motor symptoms, e.g. altered
olfactory function and erectile dysfunction. Non-motor
symptoms have gradually emerged and been accepted as
an integral part of PD.
Despite the significant advances in medical research
and the clinical management of PD during the past de-
cades, slowing its progression remains major unmet need.
Dopamine-replacement therapy (levodopa and dopamine
agonists) improves the motor symptoms and alleviates dis-
ability. In particular, levodopa remains the gold standard
of drug therapy, but it is also associated with dyskinesia,
i.e. drug-induced involuntary body movement and motor
fluctuations[15-17]. These motor complications, which usu-
ally occur after a few years of levodopa treatment, can in
turn have an adverse impact on patients’ quality of life and
contribute to the global disability. Further, symptomatic
therapy with dopamine-replacement fails to slow down or
stop the disease progression. Therefore, increasing efforts
have recently been dedicated to developing therapeutic
agents that potentially have neuroprotective or disease-
modifying effects in PD patients. The present review
provides an overview of clinical studies investigating the
natural progression of motor symptoms through the course
of PD. Furthermore, current progress on neuroprotective or
disease-modifying drug trials is reviewed and discussed.
2 Progression of motor symptoms in PD
Several studies, including placebo-controlled clinical
trials and the use of a longitudinal design[18-24], have been
conducted to investigate the changes in motor symptoms
of PD over a period of time. Motor symptoms are evalu-
ated by the Motor Examination (Part III) of the Unified
Parkinson’s Disease Rating Scale (UPDRS), with higher
scores indicating a greater severity of disease. Data ob-
tained during a 6- to 12-month placebo phase recommend
changes in motor scores as the best indicator, as there is no
treatment effect to confound interpretation of the results.
The reported changes are consistent across several trials,
with an increase of 8 to 10 points for the total UPDRS and
an addition of 5 to 6 points for the motor scores alone[18-21].
Such a change is considered to be clinically significant
due to its impact on functional disability in early PD.
Using cross-sectional analysis, a more recent study of 653
PD patients reported that the minimal clinically important
differences were estimated to be 2.3 to 2.7 points on the
UPDRS motor score and 4.1 to 4.5 points on the UPDRS
total score. These estimates are expected to assist in de-
termining clinically meaningful changes in PD progression
and the response to therapeutic interventions.
Ruiping Xia, et al. Progression of motor symptoms in Parkinson’s disease
These studies examined the progression of several
motor symptoms as an entirety. Using a longitudinal ap-
proach, Louis et al. investigated disease progression by
quantifying the rate of change of the cardinal motor symp-
toms (bradykinesia, rigidity, tremor, and postural instabil-
ity) altogether as well as separately in 237 PD patients
using the Motor Section of the UPDRS. Patients were
evaluated at baseline and at yearly intervals for up to eight
years. The results showed that the total motor scores in-
creased at an annual rate of 1.5% and at more than double
that rate (3.6%) in those who died during the follow-up
period. In addition, the sub-scores for bradykinesia, rigid-
ity and gait impairment progressed at similar annual rates
of 2.0%-3.1%, whereas the tremor sub-score remained
relatively constant over time. This finding had been previ-
ously suggested and was subsequently confirmed by a
clinical drug trial known as the Deprenyl and α-Tocopherol
Antioxidative Treatment of Parkinsonism (DATATOP)
study. More recently, Schupbach et al. examined the
progression of motor symptoms in early, untreated PD pa-
tients for a period of 12 months, by using the Motor Sec-
tion of the UPDRS as well as a modified segmental rating
of motor signs including all major joints. Each patient re-
ceived comprehensive evaluations of motor symptoms at
baseline and follow-up at 6 and 12 months. They reported
that rigidity progressed faster than akinesia/bradykinesia
and tremor, based on the UPDRS-III and the modified seg-
mental rating of motor signs.
Neuroimaging data and pathological reports have
provided the underlying explanations for these clinical
observations. It has been shown that tremor-dominant pa-
tients present a slower progression in which there is better
preservation of the nigro-striatal pathway, whereas a faster
progression occurs in the akinetic-rigid type that is accom-
panied by severe cell loss in the substantia nigra pars com-
pacta[13,30]. As evaluated by fluoropropyl-carbomethoxy-
iodophenyl-tropane (FP-CIT) single photon emission
computed tomography (SPECT) (a sensitive tool for
quantifying the striatal density of the dopamine transporter
and used for clinical purposes), tremor-dominated pa-
tients showed consistently higher FP-CIT uptake in all the
examined regions as compared to the akinetic-rigid group.
In addition, several cross-sectional imaging studies showed
a strong correlation of the dopamine transporter with glob-
al measures of motor symptoms and with specific cardinal
motor features, most notably with bradykinesia and rigid-
ity[31-34]. In contrast, most studies showed no correlation
between dopamine transporter binding and rest tremor or
action tremor[32-34]. More recently, a study in over 60 pa-
tients showed that FP-CIT uptake in the contralateral cau-
date and contralateral putamen had significant correlations
with rigidity and bradykinesia, as assessed by the UPDRS
motor scores. But the FP-CIT uptake in either caudate or
putamen had no correlation with the tremor score. This
is consistent with the evidence that reductions of striatal
density of the dopamine transporter are significantly cor-
related with the severity of rigidity and akinesia/bradyki-
nesia but not with tremor[13,33-37]. Moreover, accumulating
evidence consistently shows that the correlation between
the motor symptom of each clinical sub-type and neuronal
loss, as measured by neuroimaging, varies remarkably, and
there are distinctive patterns in the progression of motor
symptoms among different phenotypes of PD. Such varia-
tion suggests that different pathophysiological processes
and nigro-striatal pathways are represented by various sub-
types of PD.
Further, several studies have demonstrated that the
progression of motor symptoms has a nonlinear pattern
over the course of disease. The progression is faster in pa-
tients at the early stage of disease (Hoehn and Yahr stages
1–2.5) than in patients with a longer disease duration (Hoe-
hn and Yahr stages 3–5)[39,40]. This nonlinear pattern can
be explained as follows. First, clinical measures of motor
impairment might have easily reached saturation at the ad-
vanced stages of the disease, possibly due to a ceiling effect
of the UPDRS. Second, a clinicopathological study using
a longitudinal design also presented similar findings of an
exponential decline of nigral cell counts associated with
PD over time. In an earlier study by Fearnley et al.,
the micro-structure of the substantial nigra was examined
in 20 patients with varying disease durations and 36 con-
trol cases. The findings also showed an exponential loss of
Neurosci Bull February 1, 2012, 28(1): 39–48
pigmented neurons, with a 45% loss in the first decade in
the patient group whereas in the control cases, there was a
linear decline of pigmented neurons at a rate of 4.7% per
decade with aging in the substantia nigra pars compacta.
Moreover, the nonlinear progression of PD was also
supported by a longitudinal cohort study using neuroim-
aging. In that study, 31 parkinsonian patients with a
wide spectrum of disease durations and severity were
examined by serial PET imaging of striatal fluorodopa F
18 activity at a baseline visit and a follow-up visit, with a
mean interval of 64.5 ± 22.6 months between. The results
suggest that the neurodegenerative process in PD follows a
negative exponential course and slows down with increas-
ing disease duration.
3 Non-motor symptoms in PD
The motor symptoms of PD have dominated the clini-
cal picture of the disease. However, many patients with PD
also experience a series of non-motor-related symptoms
that can be presented at different stages of the disease. The
non-motor symptoms, which have attracted increasing
attention during the past couple of decades, are now con-
sidered as important elements in the clinical spectrum.
Typical non-motor symptoms include but are not limited
to, sleep disturbances, anxiety, depression, constipation,
fatigue, change or loss of smell, hallucination, and a pro-
gressive decline of cognitive ability that may lead to de-
The recognition of non-motor symptoms in PD has
stimulated much interest in research to better understand
the disease process, as well as their impact on patients’
quality of life. Several studies have shown that non-motor
symptoms can significantly impair the quality of patients’
lives and may precipitate institutionalization[44,45]. Further,
it is now known that a variety of non-motor symptoms can
precede the cardinal motor features and diagnosis of PD by
a number of years. The stage with non-motor symptoms
is often referred to as the premotor phase. In particular, ef-
forts are being dedicated to testing the significance of rapid
eye movement-related sleep disorder and olfactory dys-
function as potential biomarkers or precursors to identify
individuals at an increased risk of developing the motor
symptoms, before substantial loss of dopaminergic neurons
Apart from the association of these symptoms with the
premotor phase, various non-motor symptoms frequently
develop in the majority of patients who are at moderate
or advanced stages of PD. Non-motor symptoms can be
manifested within five years of disease onset, as indicated
by a patient self-reported questionnaire. The common
clinical signs include cognitive decline and dementia, pain,
4 Relationship between motor and non-motor
symptoms in PD
The motor symptoms have been recognized since its
first description by James Parkinson in 1817. Disability is
most commonly associated with the cardinal motor symp-
toms which are often referred to as the primary symptoms
of PD. Further, motor symptoms are more extensively in-
vestigated, and their impact on patients’ functional mobil-
ity and quality of life is well-established[50-52]. On the other
hand, evidence also suggests that non-motor symptoms
have significant impacts on patients’ quality of life[53,54].
The findings on motor and non-motor symptoms can be
investigated both clinically and from the patients’ perspec-
A recent study in 462 patients showed that both mo-
tor and non-motor symptoms contribute to health status,
as measured by the PD questionnaire[55-57]. Motor signs,
depression, anxiety, cognition, and other non-motor symp-
toms are the top five symptom domains that determine
patients’ health status. In general, the worst symptoms
deemed by patients are often different from what is per-
ceived by clinicians. To investigate the prevalence of the
most troublesome symptoms in PD experienced and per-
ceived by patients, Politis et al. assessed 265 patients by
asking each to name and rank the three worst symptoms
experienced in the previous six months. The patients were
stratified into two groups according to the duration of
disease. Subjects with less than six years of disease were
classified into the early PD group while those who had
Ruiping Xia, et al. Progression of motor symptoms in Parkinson’s disease
more than six years of symptoms were considered to be in
the advanced group. In the early group, the cardinal motor
symptoms (slowness, tremor, and stiffness) were the high-
est-ranked symptoms, followed by pain, loss of smell/taste
and mood. Patients in the advanced group ranked fluctu-
ating response to medication, mood, and drooling as the
worst complaints, followed by sleep problems, tremor, and
pain. The findings from this study suggested that the car-
dinal motor symptoms are the most prevalent complaints
in patients with early PD. Wearing-off or fluctuating re-
sponses to medication was the most troublesome complaint
in advanced group. The wearing-off phenomenon usually
refers to an earlier than expected reappearance of the cardi-
nal motor symptoms. Besides motor-related symptoms, the
non-motor symptoms pose greater challenges to patients’
daily lives at an advanced stage of the disease.
As described in Section 3, many patients with PD ex-
perience a wide variety of non-motor symptoms in addition
to motor impairments[14,59]. Some non-motor symptoms can
occur at the premotor stage whereas several other manifes-
tations co-occur with motor symptoms. For example, the
aforementioned study examining patients’ perceptions of
the three worst symptoms identified pain, mood and sleep
problems to be the most troublesome non-motor impair-
ments in both the early and advanced groups.
With respect to treatment, the classical triad of mo-
tor symptoms generally responds well to dopamine-
replacement therapy. However, non-motor symptoms are
not or not fully responsive to dopaminergic medication,
suggesting that the non-motor symptoms might be medi-
ated by non-dopaminergic pathways and non-nigrostriatal
mechanisms, such as neurodegeneration of other transmit-
ter systems in the cortex and brainstem, as well as genetic
and psychosocial factors.
5 Therapeutic interventions for motor symp-
toms in PD
A variety of pharmacological and surgical interven-
tions are available for the management of PD. Levodopa
was the first major breakthrough in treatment, and re-
mains the “gold standard” in the management of symp-
toms. Levodopa is converted into dopamine in the brain
to replenish the brain’s dwindling supply. In contrast to
levodopa, dopamine agonists, whose introduction was a
milestone in treatment, act directly on dopamine receptors
in the brain, and thus can help alleviate the symptoms.
However, after a few years’ treatment with levodopa, many
patients begin to develop motor complications, which are
broadly classified as “wearing-off reactions”, “on-off reac-
tions”, and dyskinesia. Surgical treatments have report-
edly been effective in reducing symptoms and improving
function. These include pallidotomy, thalamotomy, subtha-
lamotomy, and high-frequency deep brain stimulation
(DBS) via electrodes implanted in the globus pallidus,
thalamus, or subthalamic nucleus[61,62].
Among the motor symptoms, bradykinesia and rigidity
are most responsive to medication and surgical treatment,
followed by tremor that also shows a positive response
to the above interventions. Postural instability is gener-
ally not responsive to dopamine replacement. Numerous
physiological studies have shown the effects of dopamin-
ergic medications and DBS on reducing bradykinesia[63,64],
rigidity[65-69], and tremor[70,71] in patients with PD. The oc-
currence of falls and gait dysfunctions associated with
postural instability is an important determinant of patients’
quality of life. Given the poor responses of postural
instability to drug and surgical interventions, numerous
exercise interventions and rehabilitation programs have
emerged and been evaluated with respect to their effective-
ness on outcomes such as balance, strength, gait, walking
speed, and physical function[73-75]. Clinical studies have
shown beneficial effects of a variety of such programs
(e.g. aerobic exercise, home-based exercise intervention,
treadmill training with body weight support, and resistance
training) on improving functional mobility in patients with
PD[75-77]. The degree of improvement varies according to
the type of intervention program, length of the program, as
well as the frequency and duration of each training session.
These studies not only provide useful information in
guiding clinicians to practice evidence-based decision-
making in patient care but also lay a foundation for clinical
application and implication. Each of the cardinal motor
Neurosci Bull February 1, 2012, 28(1): 39–48
symptoms can be used as an index to assess the efficacy
of new pharmacological and surgical approaches or the ef-
fectiveness of new rehabilitation programs for PD patients,
based on their responsiveness to each of the treatment re-
6 Current progress in disease modification
Considerable research efforts have recently focused
upon the development of neuroprotective and disease-
modifying agents that are intended to slow the progression
of PD. More than a dozen randomized, controlled clinical
trials have been conducted to assess the potential neuropro-
tective effects for disease modification as summarized in a
systematic review. In that article, the authors reviewed
15 published studies on placebo-controlled trials which
tested 13 putative neuroprotective agents and enrolled
more than 4 000 participants. Among these trials were a
few well-known large clinical trials, such as the DATATOP
study that was conducted at 28 clinical sites across
North America, the Early versus Later Levodopa in PD
(ELLDOPA) study involving 32 sites in North America,
and an international study on TCH346 that was carried
out at 45 clinical sites.
The primary outcome measures applied in the above
trials were either “Time to levodopa or dopaminergic
treatment” or “Change in UPDRS”. The latter outcome
assessment included different variables, e.g. both absolute
changes in the UPDRS scores and changes in rate. The to-
tal UPDRS score was used in some trials whereas the sum
of Parts II and III (i.e., activity of daily living and motor
examination, respectively) was applied in other trials. The
results from these trials showed various outcomes, with
several trials demonstrating positive effects for neuropro-
tection, three negative effects, three equivocal effects and
the remaining trials showing neither positive nor negative
effect or a pilot trial. In brief, the disease-modifying effects
of these putative agents remain inconclusive.
Further, the use of clinical UPDRS as the outcome
measure of progression has potentially introduced a
confounding factor related to the interpretation of data,
because the UPDRS scores show improvement due to
symptomatic benefits from dopaminergic treatments,
consequently masking the underlying course of disease
progression. In particular, this could be a concern when as-
sessing patients who are in the early stages of the disease,
in which cardinal motor symptoms such as rigidity and
bradykinesia respond well to dopamine-replacement inter-
vention. In an attempt to overcome this barrier, neuroim-
aging data have been used as biomarkers to measure the
progression in trials evaluating drugs with known symp-
tomatic benefits on parkinsonian symptoms. The exemplar
trials included measurement of changes in putamenal 18 F-
fluoro-levodopa (18F-Fdopa) uptake with positron emission
tomography (PET) to assess the impact of drug treatment
upon nigrostriatal integrity in the Requip as Early Therapy
versus L-dopa-PET (REAL-PET) trial. Over 160 patients
with an early diagnosis of PD were enrolled and randomly
assigned to treatment with either ropinirole or carbidopa/
levodopa. PET imaging of 18F-Fdopa uptake showed sig-
nificantly less reduction in putamenal 18F-Fdopa uptake in
patients randomized to ropinirole (13%) compared to those
on carbidopa/levodopa (20%) when assessed at the end
of the two-year study. Such a difference is equivalent to a
34% slower loss of dopaminergic termini in the ropinirole
group than in the carbidopa/levodopa group. Despite its
potential as a surrogate biomarker, questions have arisen
about the degree to which the imaging markers truly re-
flect nigrostriatal integrity and as to whether there was any
blending effect on the imaging data resulting from the drug
A novel approach using a randomized delayed-start
design has most recently been explored in an attempt to
differentiate the disease-modifying effect from the symp-
tomatic effect. In this type of study design, patients are
randomly assigned to either putative drug or placebo group
during Phase I of the study. All patients in both groups
then receive the intervention drug in Phase II. This study
design allows for testing whether an earlier intervention is
more beneficial than a delayed intervention. A positive dif-
ference, if demonstrated, indicates the disease-modifying
effect rather than the symptomatic effect, given that both
Ruiping Xia, et al. Progression of motor symptoms in Parkinson’s disease
groups receive the same medication. The observed benefits
can therefore be attributed to the early initiation of drug
intervention, indicating the neuroprotective effect of the
The first prospective clinical trial using this novel ap-
proach was the Attenuation of Disease Progression with
Azilect Given Once-Daily (ADAGIO) study that was spe-
cifically designed to evaluate the potential of rasagiline for
disease modification. Rasagiline is an irreversible mono-
amine oxidase type-B (MAO-B) inhibitor used to treat
early and advanced PD. A possible neuroprotective effect
of rasagiline stemmed from laboratory studies in animal
models of PD[86, 87]. In the double-blind, delayed-start trial
of ADAGIO, a total of 1 176 early untreated PD patients
were enrolled and randomly assigned into either the inter-
vention or placebo group. The trial consisted of Phase I
for 36 weeks followed by Phase II for another 36 weeks.
The results showed consistently slower rates of worsening
in the UPDRS scores associated with early-start treatment
with rasagiline at 1 mg per day, suggesting a possible dis-
ease-modifying effect at this dose. However, the authors
pointed out that the results should be interpreted with cau-
tion due to concerns such as a high dropout rate during the
placebo phase, potential misdiagnosis associated with early
PD and other related factors. Despite these limitations, the
ADAGIO trial is regarded as a landmark partly because of
its use of a novel design that offers the best possible means
to test putative neuroprotective agents at present.
The progression of motor symptoms in PD is closely
associated with the progressive neurodegeneration in ni-
grostriatal pathways. In addition, multiple other factors
contribute to the progression of global disability, converging
from treatment-induced motor complications, evolution
of axial motor symptoms poorly responsive to levodopa,
and a large variety of non-motor symptoms. Significant
advances have been made in increasing our understanding
of the disease process and in clinical interventions. Ef-
fective treatment can be developed only if the origin and
pathogenesis of PD have been revealed. Insights from
animal and clinical studies have provided putative agents
for neuroprotection or disease modification, with some
having been tested in clinical trials and others on the way.
Currently, therapeutic agents with a strong disease-modifying
effect are not available. Substantial momentum in this area
has, however, made it clear that therapeutic strategies with
disease-modification potential are on the horizon.
Acknowledgements: This work was supported by the
National Institutes of Health (R15-HD061022 and R15-
HD061022-S1) and the Faculty Development Fund of the
School of Pharmacy and Health Professions, Creighton
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