health-related Quality of Life, economic cost,
Parkinson’s disease (Pd) is the second most common neurodegen-
erative disorder, marked by increasing movement-related disability,
Parkinson’s disease (PD) is the second most com-
including tremor and bradykinesia, impaired balance and coordina-
mon neurodegenerative disorder, marked by pro-
tion, and cognitive changes.1 it affects up to 1 million people in the
gressive increases in movement-related disability,
united States and up to 5 million worldwide.1 The prevalence of Pd
impaired balance, and nonmotor symptoms. Its prevalence in the United States is expected to
increases with age, with approximately 1% of those aged 60 years
double within the next 20 years as the percentage
or older affected, 4% or more of those aged 80 years or older,2 and
of the elderly in the population grows. Patients
approximately 5.2% of those in nursing homes.3 given the growing
with PD have twice the direct medical costs of
elderly population in the united States, the number of individuals
those without PD, the majority of which occur later in the disease as disability and therapy-related
complications increase. Greater awareness of a
Such an increase will place a significant burden on healthcare
prodromal/premotor stage of the disease, efforts
systems and caregivers given the progressive nature of Pd, associ-
toward early and accurate diagnosis, and the continuous refinement of treatment paradigms
ated disability, and significant caregiving required in the later stages
provide an opportunity for discussion on the use of
of the disease. With the expected increase in Pd prevalence, it can
potential disease-modifying agents to slow or halt
be anticipated that the disease will continue to exact a significant
the progression of motor and nonmotor disabil-ity. Such compounds could not only significantly
direct and indirect economic cost. Thoughtful consideration into
improve patient and caregiver quality of life, but
treatment decisions can result in more optimal healthcare utiliza-
substantially reduce direct and indirect costs. To
tion without sacrificing health-related quality of life (hrQOL) and
date, numerous compounds have been evaluated
in clinical trials, including coenzyme Q10, creatine, levodopa, pramipexole, rasagiline, ropinirole, and selegiline. None has demonstrated irrefutable and
Economic Costs of PD and Impact on
enduring disease-modifying qualities, although
Health-Related Quality of Life
the best available clinical evidence appears most promising for rasagiline.
Overall, the annual economic impact of Pd in the united States
(Am J Manag Care. 2010;16:S87-S93)
is estimated at $10.8 billion, 58% of which is related to direct
medical costs.5 Annual direct medical costs per patient with Pd are
estimated to Managed Care
be between $10,043 and $12,491, &
Healthcare Communications, LLC
that of patients without the disease.5,6 Prescription drugs account for approximately 14% to 22% of costs, with nursing home care the
largest component at approximately 41%. Annual indirect costs,
including lost workdays for patients and caregivers, are estimated at
As important as economic costs are to any discussion of
Pd-related resource utilization, it is also critical that payers and pro-
viders consider the significant impact the disease has on hrQOL.
hrQOL assesses an individual’s perceived effect of the illness on
their physical, psychological, and social daily lives.7 it is important
in determining the effectiveness of therapies for Pd at both the
For author information and disclosures, see end of text.
individual and population levels.8 for managed care providers, it presents an important parameter to measure the effectiveness
n The AmericAN JOurNAL Of mANAged cAre n
of management strategies and quality of care.7 hrQOL
a resting tremor, and this has been reported to be prognostic
measures are also important in assessing the value of drug
of a more rapidly progressive disease course.26 As the disease
therapy, particularly for chronic conditions such as Pd, and
progresses, patients exhibit disability due to bradykinesia,
in determining the appropriate placement of medications on
rigidity, gait and balance difficulty, and falls.24 Additionally,
dopaminergic-related side effects from medications become
As would be expected for any chronic and progres-
more problematic. in more advanced stages of the disease,
sively worsening disorder, Pd has a significant impact on the
disabling cognitive symptoms, such as dementia, are more
hrQOL for both patients and their caregivers.11 in a large
Veterans Administration cohort, patients with Pd exhibited
Several assessment and rating scales provide clinically
lower scores on the physical and mental health dimensions
important information on changes in Pd severity and dis-
of hrQOL compared with patients with 8 other neurologic
ability. These include the unified Parkinson’s disease
or chronic conditions, including diabetes, congestive heart
rating Scale (uPdrS), which is undergoing revision to
failure, angina/coronary heart disease, and stroke.12 Of note,
better account for nonmotor symptoms, Webster’s columbia
nonmotor disability, particularly depression, insomnia, and
university rating Scale (curS), Northwestern university
other mental health factors, appear to have a greater negative
disability Scale (NudS), and the hoehn and Yahr scale.27
effect on hrQOL than motor deficits.8,13-15
A recent analysis correlated disability with the uPdrS and identified specific motor and total scores to assist clinicians
Etiology and Clinical Course of PD
in determining clinically meaningful changes in Pd progres-
Aging, in addition to multiple other factors, appears to
contribute to the pathoetiology of Pd. Approximately 5% to 10% of patients demonstrate a familial pattern of the disease,
Implications of Prodomal/Premotor Stage
some of which are associated with linkages to a dozen differ-
Pd is comprised of motor and nonmotor signs and
ent gene mutations.16 environmental factors likely interact
symptoms. it is recognized that extranigral neuropathologic
with genetic factors to increase the risk of Pd, including
changes precede the degeneration of nigrostriatal dopamin-
herbicide or pesticide exposure.17-20 interestingly, epidemio-
ergic neurons; thus, nonmotor features antedate the onset
logic studies have consistently associated an inverse correla-
of motor features. however, diagnostic criteria for Pd are
tion between cigarette smoking and coffee consumption for
validated based on motor features. Premotor clinical features
include autonomic dysfunction (impaired olfaction, cardiac
The brains of individuals with Pd are marked by degen-
sympathetic denervation, urinary disturbances), gastrointes-
eration and loss of dopaminergic neurons in the substantia
tinal disturbances (constipation), neuropsychiatric disorders
nigra.1 Nondopaminergic pathways are also involved, includ-
(depression, mild cognitive impairment, rBd), and sensory
ing cholinergic and norepinephrine neurons in the basal fore-
disorders (pain, restless legs syndrome). Such symptoms may
brain, serotonin neurons in the midbrain raphe, and other
occur up to 10 years prior to motor symptoms and diagno-
neurons in the brain stem, spinal cord, and peripheral auto-
sis.29-32 The table
describes nonmotor symptoms that may be
nomic nervous system. Pathology in many of these neuronal
present in the premotor stage of Pd.
systems likely contributes to the nonmotor manifestations of
There are several stages related to neuronal changes, with
earlier stages occurring in areas other than the substantia
more recently, it has been postulated that Pd may be
nigra. As Braak and his coauthors noted: “Were it to become
a prion disorder given the prion-like behavior of alpha-
possible to diagnose Pd in the presymptomatic stages 1 or
synuclein protein aggregates. These aggregates comprise a
2, and were a causal therapy to become available, the subse-
significant portion of the Lewy bodies that are a cellular
quent neuronal loss in the substantia nigra could be entirely
prevented.”32,33 By the time patients are diagnosed, however,
The clinical course of Pd often begins with nonmotor
substantial neuronal damage has already occurred in the
symptoms such as constipation, hyposmia (reduced sense
substantia nigra, with dopamine levels at least 30% to 40%
of smell), and rapid eye movement (rem) sleep behavior
disorder (rBd). Patients are usually not diagnosed, however,
greater awareness and recognition of the presence of
until they exhibit obvious motor symptoms, consisting of
premotor symptoms of Pd have raised the possibility of
resting tremor, rigidity, and/or slowness of movement (bra-
very early diagnosis (before appearance of motor features).
dykinesia).1,24,25 About one third of patients do not develop
imaging studies utilizing dopamine transporter tracers and
health-related Quality of Life, economic cost, and implications of early Treatment
Symptoms in the Premotor Phase of Parkinson’s Disease (PD) and Their Neuropathologic Substrates
Well Documented in the
Nonmotor Symptoms in PD
pain, apathy, fatigueCognitive dysfunction
Cognitive impairment can be considered as a possible premotor manifestation of PD. When severe cognitive impairment (dementia) occurs before
motor symptoms, it is regarded, arbitrarily, as the early manifestation of dementia with Lewy bodies and not as a premotor manifestation of PD.
Adapted with permission from Tolosa E, et al. Neurology
. 2009;72(7 suppl):S12-S20.
nigral ultrasound methods demonstrate the potential for
direct medical costs occur in the later stages of the disease.
use in earlier diagnosis.34 given increased knowledge of
Part of that is related to the levodopa-induced dyskinesia
the premotor phenotype of Pd, a battery of tests including
that patients develop after several years on the drug. A
assessment of nonmotor features, olfactory testing, cardiac
recent review of studies found that approximately 25% of
scintigraphy, and neuroimaging may one day provide a
all patients develop levodopa-related dyskinesia between
means of reliably diagnosing Pd at an early stage of the
2.5 and 3.5 years, and up to 39% between 4 and 6 years.35
disease. ideally, then, disease-modifying (neuroprotec-
Semiannual direct medical costs were more than double in
tive) therapies designed to slow or halt disease progression
patients with Pd experiencing severe dyskinesia compared
would be initiated. Although disease-modifying therapies
with those without motor complications.36 Levodopa-induced
may provide a benefit in moderate-to-advanced Pd, ini-
dyskinesia also has a significant negative impact on patient
tiation of therapy in early disease would provide greater
quality-of-life scores and depression severity.36 in addition,
approximately 15% to 20% of patients on dopamine agonists
Such approaches could result in significant direct and
exhibit impulse control disorder behavior (eg, gambling,
indirect cost savings as well as improve patient and care-
hypersexuality), imposing a significant economic and quality-
giver quality-of-life indicators. As noted earlier, the bulk of
of-life burden on patients and their caregivers.37
n The AmericAN JOurNAL Of mANAged cAre n
Numerous pharmacologic medications are available to
The AdAgiO (Attenuation of disease Progression with
treat early Pd, including amantadine, anticholinergic agents,
Azilect given Once-daily) trial is the largest such study. it
dopamine agonists, levodopa, and monoamine oxidase type
was a prospective, multicenter, placebo-controlled, double-
B (mAO-B) inhibitors. Additional detail on early phar-
blind clinical trial with a delayed-start design developed to
macologic treatment is located in the article by hauser38
assess the efficacy of rasagiline as a disease-modifying com-
in this supplement. however, none are routinely used or
pound in 1176 patients with early, nondisabling Pd. The
recommended for treatment in patients with asymptomatic
AdAgiO trial was initiated based on results from a prelimi-
motor Pd.39,40 instead, treatment is traditionally delayed until
nary trial which suggested that rasagiline given early in the
patients exhibit functional impairment. This limits exposure
disease might have disease-modifying benefits.48
to the adverse effects of antiparkinson medications as well
Patients in the AdAgiO trial (mean duration of disease
as delays the long-term negative effects of levodopa-induced
from the time of diagnosis, 4.5 months; baseline mean total
motor complications described earlier.41
uPdrS score, 20.4) who received rasagiline 1 mg/day for 72
given the significant economic burden of Pd and knowl-
weeks (the early-start group) exhibited greater improvement
edge of the premotor phase, there is significant interest in
(ie, a smaller mean increase) in the uPdrS score between
identifying disease-modifying compounds that can be initi-
weeks 12 and 36 than the placebo group (thus reconfirm-
ated very early in the disease, possibly before any functional
ing efficacy relative to placebo), and less worsening overall
motor impairment or disability appears. Not to be dismissed,
between baseline and week 72 than the delayed-start, active-
in patients with moderate-to-advanced stages of Pd, thera-
treatment group (thus confirming that earlier initiation of
pies that delay the onset of gait and balance impairment and
rasagline is associated with better outcomes compared with
cognitive impairment will also allow patients to function inde-
pendently for a longer period of time, thus reducing costs and
Not all of the end points were met with a 2-mg/day dose
preserving hrQOL.36 evidence already shows that initial ther-
of rasagiline.49 however, a post hoc subgroup analysis showed
apy with nonlevodopa agents is cost-effective, prolongs time to
that patients with the highest quartile baseline uPdrS
levodopa initiation, and delays the onset of dyskinesia.42,43
scores (>25.5) who received rasagiline 2 mg/day did meet all
Numerous targets for neuroprotection have been identi-
primary end points. Among patients given rasagiline 1 and
fied, including oxidative stress, neuroinflammation, protein
2 mg/day, those in the early-start (active treatment) groups
aggregation and misfolding, excitotoxicity, apoptosis, and loss
had significantly less worsening of uPdrS scores between
of trophic factors.44 clinical trials to test disease modification,
baseline and week 72 (-3.40 points and -3.63 points, respec-
however, have been particularly difficult to design and conduct.
tively) compared with the delayed-start (active treatment)
Among the challenges are the need to identify and recruit large
= .04 for both). Patients with the highest quartile
numbers of untreated patients with early Pd; heterogeneity of
baseline uPdrS scores given rasagiline 1 mg/day and 2 mg/
criteria used to evaluate disease progression; lack of a specific
day also demonstrated significantly greater improvement of
biomaker of disease progression; lack of agreement on the mag-
scores from baseline to week 36 (-6.43 points and -7.13
nitude of effect that should be expected of a disease-modifying
points, respectively; P
<.001 vs placebo); these were clini-
agent; and difficulty differentiating between symptomatic and
cally important differences.28 Of note, in clinical practice, the
disease-modifying effects of the intervention.45,46 To overcome
majority of patients with early Pd who seek medical atten-
this last barrier, researchers have utilized a delayed-start design
tion for their symptoms would fall into this upper quartile
in which patients are randomized to begin treatment with the
subgroup. Additionally, the uPdrS score in this subgroup is
study drug or placebo for a certain amount of time, after which
representative of that in other clinical trials involving early
the placebo group is switched to the study drug and followed,
Pd patients. There were no significant differences in adverse
along with the intervention group, for the remainder of the
events between the 2 groups. Additional detail and discussion
study. A sustained difference (improvement) in the early-start
of the AdAgiO trial appear in the article by hauser38 in this
group after the second phase of the trial suggests that early
treatment confers a benefit that would not appear if the drug
A later analysis of the trial data demonstrated that rasagi-
were introduced later in the disease (delayed start).47
line also reduced the progression of nonmotor symptoms (eg, altered mood, apathy, cognitive impairment, sleepiness, pain,
Clinical Trials With Disease-Modifying Agents
fatigue, urinary problems) as assessed with the movement
To date, at least 23 trials with potential disease-modifying
disorder Society (mdS)-uPdrS.50 The efficacy and safety
agents have been conducted or are ongoing.46
results of AdAgiO have spurred a growing number of clini-
health-related Quality of Life, economic cost, and implications of early Treatment
cians to consider beginning rasagiline treatment in function-
Therapy in Parkinson disease) trial, levodopa (150, 300,
ally unimpaired patients (ie, not yet requiring levodopa or
and 600 mg/day) was significantly better than placebo in
reducing the worsening of Parkinson’s symptoms at week 42
The outcomes associated with rasagiline should not be
<.001).58 however, patients in the levodopa group had
considered a class effect of mAO-B inhibitors. Specifically,
significantly more adverse events (including dyskinesias)
the results of AdAgiO cannot necessarily be extrapo-
than those in the placebo group. results from the eLLdOPA
lated to selegiline, another available mAO-B inhibitor.
trial are described in detail in the article by hauser38 in this
Selegiline is metabolized to the amphetamine derivatives
L-methamphetamine and L-amphetamine,51 which are pres-
The reAL-PeT (requip as early Therapy versus L-dopa-
ent in sufficient concentrations to produce side effects in
PeT) trial used f-dopa positron emission tomography (PeT)
patients with Pd. Additionally, chronic exposure to these
as a biomarker of neuronal degeneration to evaluate the
compounds has been shown to induce neurotoxicity in ani-
effects of ropinirole versus carbidopa/levodopa on disease
mal and laboratory studies,52,53 and studies demonstrate that
progression.59 After 2 years, the ropinirole group demon-
L-methamphetamine inhibits the potential neuroprotective
strated significantly greater preservation in biomarker uptake
activities of selegiline.54 rasagiline, on the other hand, is
in the putamen and substantia nigra than the levodopa group
devoid of amphetamine-derived or neurotoxic metabolites.
= .022). however, in contrast with the biomarker results,
Thus, the pharmacologic differences between rasagiline and
the clinical benefit in the levodopa group was significantly
selegiline preclude any meaningful comparisons of clinical
Pramipexole was evaluated in the PrOud (Pramipexole
Selegiline was evaluated as a possible disease-modi-
on underlying disease) trial, a placebo-controlled, delayed-
fying agent in dATATOP (deprenyl and Tocopherol
start study designed to evaluate the potential disease-modifying
Antioxidative Therapy of Parkinsonism), a large trial
effect of pramipexole 1.5 mg/day. Preliminary results reported
designed to assess the ability of early intervention with
as an abstract reported no significant difference in uPdrS
selegiline or tocopherol to postpone levodopa initiation in
scores at final study visit (after 15 months) between the early-
800 patients. While tocopherol showed no benefit, patients
and delayed-start pramipexole groups (P
= .65) and no differ-
receiving selegiline as monotherapy were able to significantly
ence in loss of striatal dopaminergic neurons (P
delay the need for levodopa therapy compared with the group
Several compounds have been tested in futility trials and
receiving placebo and demonstrated a significant reduction
warrant additional investigation, including coenzyme Q10
in disease progression as measured by the uPdrS (P
and creatine.61,62 coenzyme Q10 is currently being evalu-
vs placebo).55 however, upon completion of the study, a
ated as a potential disease-modifying agent in an ongoing
subset of patients given placebo were initiated on open-label
16-month clinical study known as Qe3.63 creatine is also
selegiline (ie, received delayed-start selegiline), and uPdrS
currently being evaluated as a potential disease-modifying
outcome scores in this group were no different than in the
agent in a large ongoing 5-year clinical trial (known as LS-1)
original selegiline monotherapy group. Thus, the benefits
sponsored by the National institute of Neurological disorders
appear to be largely related to the symptomatic effects of the
and Stroke as part of the NeT-Pd (Nih exploratory Trials in
drug rather than to disease-modifying effects.56
A trial from the Swedish Parkinson Study group also
demonstrated a delay of levodopa initiation with selegi-
line.57 in the second phase of this study (n = 140), patients
The progressive, debilitating nature of Pd results in
who received long-term selegiline therapy in combination
significant direct and indirect medical costs for providers,
with levodopa for 5 years had significantly better uPdrS
patients and their families, and society as a whole. Such costs
outcomes compared with patients who received only
will only grow more extensive as the population ages and the
levodopa.43 Additional detail and discussion of the clini-
prevalence of the disease increases. An increasing awareness
cal trials with selegiline appear in the article by hauser38
of the presence of a premotor phase of the disease, in which
early signs of Pd may be present as much as a decade before
Other compounds that have undergone clinical testing for
the classic tremor and other movement-related symptoms,
disease modification in Pd or are still being evaluated include
gives new urgency toward the identification of prospective
levodopa and the dopamine agonists pramipexole and ropin-
agents that may be disease modifying. Several agents have
irole. in the eLLdOPA (earlier versus Later Levodopa
been tested or are being tested as disease-modifying agents in
n The AmericAN JOurNAL Of mANAged cAre n
Pd, including coenzyme Q10, creatine, levodopa, pramipex-
impacting on quality of life in Parkinson’s disease: results from
ole, rasagiline, ropinirole, and selegiline. None of these drugs
an international survey. Mov Disord.
2002;17(1):60-67.15. Ravina B, Camicioli R, Como PG, et al.
The impact of depressive
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however, the best available evidence suggests that rasagiline
holds promise in the treatment of early Pd.
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Etiology and pathogenesis of Parkinson disease.
department of Neurology, Loma Linda university,
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