NEUROLOGI CAL UPDATE

Parkinsons disease: recent advances

Regina Katzenschlager
Received: 5 March 2014 / Accepted: 5 March 2014 / Published online: 1 April 2014
Springer-Verlag Berlin Heidelberg 2014
Abstract While a curative treatment for Parkinsons
disease remains elusive, our understanding of disease
mechanisms as well as preclinical and pre-motor early
manifestations has improved greatly over the past years.
An agent with proven disease modifying properties has not
yet been identied but symptomatic treatment options for
affected patients have improved. For patients with motor
complications, this includes invasive approaches such as
deep brain stimulation and continuous device-aided drug
delivery. The many facets of non-motor problems patients
are faced with have nally been fully recognized and have
become the target of treatment trials, as have been non-
pharmacological approaches.
Keywords Parkinsons disease Symptomatic treatment
Disease mechanism
Introduction
This article continues a series of updates on neurological
conditions published in the Journal of Neurology which are
based on selected recent publications, and focuses on new
developments in Parkinsons disease (PD). Our under-
standing of disease mechanisms underlying this progres-
sive neurodegenerative disorder has improved in the past
few years, as have symptomatic treatment options.
Research efforts increasingly target pre-motor manifesta-
tions as well as the management of non-motor problems.
Disease mechanism
An increasing body of evidence is pointing toward prion-
like mechanisms as potentially underlying the spread of the
neurodegenerative process by seeding abnormally folded
proteins. Fibrils derived from recombinant alpha-synuclein
have been shown to enter neurons and to induce the
recruitment of soluble endogenous alpha-synuclein into
Lewy body-like inclusion bodies, resulting in neuronal
death [27]. Further studies have recently supported the
pathogenicity of alpha-synuclein: Nigral Lewy body-enri-
ched fractions containing alpha-synuclein were puried
from post-mortem brains of PD patients and inoculated into
the substantia nigra or striatum of wild-type mice and
macaque monkeys [18]. In contrast to control animals,
which had received non-Lewy body alpha-synuclein from
the same patients, Lewy body-derived human alpha-syn-
uclein was internalised within host neurons, accumulated
within nigral neurons, and spread to interconnected areas.
This triggered the pathological conversion of endogenous
alpha-synuclein and subsequent progressive nigrostriatal
neurodegeneration. The spread of pathological alpha-syn-
uclein therefore appears to play an important role in the
progression of PD, and Lewy bodies likely represent a
protective mechanism. This hypothesis is supported further
by evidence from animal models of multiple system atro-
phy (MSA), pointing toward a similar mechanism [26].
Biomarkers, risk factors and pre-motor manifestations
Clinical diagnostic criteria and biomarkers
The clinical diagnostic criteria for PD are currently being
re-evaluated in view of the heterogeneity of the genetic and
R. Katzenschlager (&)
Department of Neurology, Karl Landsteiner Institute for
Neuroimmunological and Neurodegenerative Disorders,
Donauspital/Danube Hospital, Vienna, Austria
e-mail: regina.katzenschlager@chello.at
1 3
J Neurol (2014) 261:10311036
DOI 10.1007/s00415-014-7308-9
molecular changes, the variability of the clinical features
and disease courses as well as the long period of time,
termed pre-motor, in which a number of non-motor
symptoms occur [15]. With the advances in the eld of
genetics, it appears likely that in the future, PD will be
considered to be several diseases with similar and over-
lapping clinical phenotypes [1]. While the disease can be
attributed to a single genetic cause in only a small per-
centage of patients at present, the contribution of a genetic
predisposition is being explored further [25]. No denite
biomarker has been established, but this will become
increasingly important as the eld of research into disease-
modifying strategies develops, and in particular once
effective disease modifying drugs become available. An
example of a potential biomarker is the recent nding of
low concentrations of Ab and P-tau in the cerebrospinal
uid (CSF) of patients with very early PD [13].
Depression
In a retrospective study, 4,634 patients with depression and
18,544 matched control patients were observed for a
maximum of 10 years to determine the rates of new-onset
PD, and to identify the predictors of PD. During the
10-year follow-up period, 66 patients with depression
(1.42 %) and 97 control patients (0.52 %) were diagnosed
with PD. After adjusting for age and sex, patients with
depression were 3.24 times more likely to develop PD
(95 % CI 2.364.44, p \0.001) than controls [24].
Idiopathic rapid-eye-movement (REM) sleep behaviour
disorder (IRBD)
Idiopathic rapid-eye-movement (REM) sleep behaviour
disorder (IRBD) is a parasomnia characterised by dream-
enacting behaviours such as talking, screaming, thrashing,
and falling out of bed, which are due to a loss of the
physiological atonia (loss of muscle tone) during REM
sleep. Several prospective reports had strongly suggested
that many patients with IRBD go on to develop a neuro-
degenerative disorder over time. Long-term follow-up data
from a cohort of IRBD patients have recently been pub-
lished [12]. Of the 44 participants from the original cohort,
36 (82 %) had developed a dened neurodegenerative
syndrome by the 14-year assessment (16 patients were
diagnosed with PD, 14 with dementia with Lewy bodies
(DLB), one with multiple system atrophy, and ve with
mild cognitive impairment). The rates of survival without
neurological disease from the time of the diagnosis of
IRBD were: 65.2 % at 5 years, 26.6 % at 10 years, and
7.5 % at 14 years. All four remaining patients free from
neurological disease had decreased striatal dopamine
transporter tracer uptake, one had substantia nigra
hyperechogenicity, and two had impaired olfaction. In
three patients, the clinical diagnoses of PD and DLB were
conrmed by neuropathological examination. Neuronal
loss and Lewy pathology were found in the brainstem
nuclei that regulate REM sleep atonia. The ndings indi-
cate that IRBD is either a risk factor, or more likely, a
prodromal phase of a Lewy body disorder, making it highly
suited for inclusion in screening batteries to test disease-
modifying strategies.
Treatment
Disease modication
Following the delayed-start trial of the MAO-B inhibitor
rasagiline in de novo PD patients, which had suggested
a potential disease modifying effect for the 1 mg dose
[17], no further clinical studies of disease modication
have as yet shown encouraging results. The dopamine
agonist pramipexole was also investigated in a delayed-
start design trial including 535 patients with early PD, at
a dose of 1.5 mg daily (PROUD Study; [20]). Patients
were randomised to receiving pramipexole immediately
or with a 9-month delay (6 months if deemed clinically
necessary). No signicant differences between early and
delayed pramipexole were found in the primary out-
come, the total score on the unied PD rating scale
(UPDRS), or in the imaging outcome, dopamine trans-
porter SPECT.
Motor complications
Dopaminergic replacement therapies signicantly improve
motor function in most patients with PD. However, long-
term levodopa therapy is frequently associated with trou-
blesome motor uctuations and drug-induced involuntary
movements (dyskinesias).
Deep brain stimulation
High-frequency stimulation of the subthalamic nucleus or
globus pallidus (deep brain stimulation, DBS) greatly
improves parkinsonian motor problems and allows a sub-
stantial reduction in oral medication. Robust evidence
exists for benecial effects of DBS on refractory motor
uctuations and dyskinesias. A multi-centre study
(EARLY-STIM) was set up to determine whether DBS
would lead to greater benets if performed at an earlier
stage of the illness, while psychosocial factors are still
largely intact [21]. In this study, 251 patients with onset of
motor complications within the previous 3 years (mean
age, 52 years; mean disease duration, 7.5 years) were
1032 J Neurol (2014) 261:10311036
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randomised to DBS versus strictly standardised best med-
ical treatment. Blinded assessments were carried out, but
patients were unblinded. At 2 years, signicantly greater
improvements were found in the primary outcome mea-
sure, quality of life, assessed by PDQ-39 (-7.8 points in
the DBS arm versus ?0.2 points in the medical arm,
p \0.002), and in the secondary outcomes of motor dis-
ability, activities of daily living, motor complications, and
time with good mobility and no dyskinesias. Serious
adverse events related to surgical implantation or to the
device occurred in 17.7 %. Suicides occurred in both arms
(two on DBS, one on medical treatment). The authors
concluded from the ndings on motor function and quality
of life that DBS should routinely be considered earlier than
it is now, where it is often offered to patients after pro-
longed attempts to adjust oral medication and after irre-
versible changes in the patients professional and personal
lives have occurred. While the EARLY-STIM study cer-
tainly contributes to the basis on which treatment choices
will be discussed with patients in the future, it should be
kept in mind thatas with all carefully designed and
performed randomised-controlled studies, but particularly
so in the case of this surgical studythe patients entered
into this trial do not necessarily reect the general popu-
lation of patients with refractory motor complications, who
often would not have fullled the inclusion criteria due to,
e.g., age, comorbid conditions, concomitant medication, or
cognitive function. The relatively high suicide rate (com-
pared to the low background rate in PD) also suggests
possible differences in the personalities or in expectations
between patients who would normally be offered DBS and
those selected for EARLY-STIM [4]. In addition, while
performing double-blind trials involving surgery poses
logistical and ethical difculties, the fact that this study
was not blinded (although the assessments were carried out
by blinded raters) also detracts from the generalisability of
the ndings.
Continuous drug delivery
Although our understanding of the mechanisms underlying
motor complications remains incomplete, discontinuous
drug delivery is thought to be involved. While striatal
dopamine release is relatively stable under physiological
conditions, substitution with a short half-life drug such as
levodopa is associated with oscillating dopamine concen-
trations that are believed to induce maladaptive changes in
basal ganglia motor circuits. Several uncontrolled studies
had suggested that switching patients with refractory motor
complications from oral to continuous treatment might
improve motor uctuations and possibly also dyskinesias.
The rst randomised, placebo-controlled study of
continuous pump delivery of a dopaminergic drug in this
clinical scenario was published recently [16]. In this
12-week study, all 71 patients underwent gastrostomy and
were randomised to intrajejunal or oral immediate-release
levodopa in a double-dummy design. The degree of
improvement with intrajejunal levodopa [1.91 h less OFF
time per day than with oral levodopa (95 % CI -3.05 to
-0.76, p = 0.0015)] is smaller than previously reported in
uncontrolled studies, but the results very likely reect true
superiority of continuous intraintestinal delivery of levo-
dopa. The magnitude of decrease in OFF-time from base-
line (-4 h) exceeds that reported for any agent tested so
far; moreover, quality of life improved signicantly. The
conclusions on dyskinesia that can be drawn from the study
are less rm. Included patients had relatively little baseline
dyskinesia and there was little change in both arms.
Moreover, no measure of dyskinesia severity was
employed. Even so, the ndings strongly suggest a clinical
benet, as there was a signicantly greater increase in ON
time without troublesome or without any dyskinesia in the
infusion group. The impressive symptomatic effects that
can be achieved with intrajejunal levodopa come at a price,
however [14]. This procedure is associated with risks and
requires the insertion of a percutaneous gastrojejunostomy
tube. In the placebo-controlled study, 97 % of patients
experienced at least one adverse event, and in 89 %, a
complication related to the device occurred. Three patients
discontinued due to adverse events; in one case this was
peritonitis. While most adverse events were mild or mod-
erate and resolved, the risk of surgical and device-related
complications must be taken seriously. In addition, several
reports have linked levodopa exposure to peripheral neu-
ropathy [8], and weight loss and possible malabsorption
have also been observed. This highly effective but invasive
treatment should only be used in the setting of expert
movement disorder centres closely collaborating with
gastroenterology units.
The relative efcacy and safety of the three currently
available device-aided and invasive treatments for motor
complications in PD, DBS, intrajejunal levodopa and
subcutaneous infusion of the dopamine agonist apomor-
phine have not been investigated in randomised studies.
While level 1 evidence is now available for DBS and for
intrajejunal levodopa, a randomised, placebo-controlled
study of apomorphine infusion is currently underway.
Non-motor problems
The impact of non-motor problems that PD patients face
has nally been fully recognised over the past years [5].
These include neuropsychiatric and dysautonomic prob-
lems, pain and non-motor uctuations.
J Neurol (2014) 261:10311036 1033
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Depression
Depression has been shown to have an important impact
on quality of life in PD patients. To evaluate the efcacy
of a selective serotonin reuptake inhibitor and a serotonin
and norepinephrine reuptake inhibitor, 115 patients were
randomised to paroxetine (at a maximum dose 40 mg per
day), venlafaxine (maximum 225 mg) or placebo [19].
Patients met DSM-IV criteria for a depressive disorder, or
operationally dened subsyndromal depression. The pri-
mary outcome measure was change in the Hamilton
Rating Scale for Depression from baseline to week 12.
Treatment effects (relative to placebo) were 6.2 points
(97.5 % CI 2.210.3, p = 0.0007) in the paroxetine group
and 4.2 points (97.5 % CI 0.18.4, p = 0.02) in the
venlafaxine group. No changes were seen in motor
function. This study provides evidence for efcacy and
safety for drugs from two classes that are frequently used
in clinical practice for depression associated with PD and
for which high level evidence had previously been
missing.
Psychosis
Among the many non-motor problems affecting patients
with PD, psychosis is particularly relevant, as it represents
a great burden to caregivers and increases the risk that a
patient can no longer be looked after at home, but will
move to a nursing home. While the cholinesterase inhibitor
rivastigmine may relieve psychotic symptoms in PD
patients, (Emre 2004) it is not licensed for this indication,
and neuroleptics often become necessary. Among the
available antipsychotics, only clozapin has been classied
as being effective in PD patients [23]; however, specialised
monitoring is required due to the risk of agranulocytosis.
Quetiapine, which is used more commonly in clinical
practice, as it does not carry this risk, does not have evi-
dence for efcacy in PD-related psychosis. All classical
neuroleptics, but also olanzapine and several other atypical
neuroleptics, have been shown to lead to considerable
motor worsening in PD patients. Therefore, there is an
urgent clinical need for additional therapeutic options for
psychosis in PD. Pimavanserin is a selective serotonin
5-HT2A inverse agonist and was investigated at a dose of
40 mg per day in a 6-week, randomised, double-blind,
placebo-controlled study in 199 PD patients with psychosis
[3]. The design included a 2-week lead-in phase to limit the
placebo response, which has been shown to be high in PD.
The primary outcome was antipsychotic benet as assessed
by independent raters with the PD-adapted scale for
assessment of positive symptoms (SAPS-PD). Pimavans-
erin was associated with a -5.8 decrease in SAPS-PD
scores compared with -2.7 for placebo (95 % CI for
difference -4.9 to -1.2, p = 0.001). Pimavanserin was
well tolerated without signicant safety concerns or
worsening of motor function. With this potentially
improved safety prole compared to other neuroleptics,
pimavanserin might turn out to be useful for the treatment
of patients with PD and psychosis. In fact, it might help
prevent progression to more severe forms of psychosis, as
use of neuroleptics has been linked to less progression in
the severity of neuropsychiatric problems in PD [11].
Physical therapy in PD
The area of non-pharmacological interventions for motor
problems in PD has been recognised as potentially
important, and these approaches are now being investigated
in randomised trials. While many of the reports of various
interventions have methodological limitations, including a
lack of blinding, physical therapy as a whole was classied
as likely efcacious by the Evidence Based Medicine Task
Force of the International Parkinson and Movement Dis-
order Society [10].
The therapeutic methods investigated vary widely and
have included a type of physiotherapy termed BIG,
which is based on the principles of Lee Silverman voice
training and focuses on high amplitude movements [6].
Other randomised trials have investigated, among other
approaches, dancing, tai chi, qigong, treadmill training, and
acoustic cueing [10], and an increasing number of reports
has been published more recently [2, 9, 22]. While meth-
odological issues remain, these studies largely conrm the
overall encouraging results for physical therapy in patients
with PD.
Summary
PD remains a relentlessly progressive neurodegenerative
disorder, with patients increasingly troubled by motor and
non-motor problems as the disease progresses. The search
for an intervention that may slow or halt this process is
therefore of utmost importance. This goal has remained
elusive, but a number of pharmacological and non-phar-
macological treatments that have been reported or inves-
tigated in recent years have helped to improve patients
quality of life.
In addition, very early diagnosis has improved.
Screening batteries involving a number of risk factors and
early non-motor signs have been identied, and potential
biomarkers are being explored. All of these will become
particularly important once a strategy with disease-modi-
fying properties becomes available.
Conicts of interest None.
1034 J Neurol (2014) 261:10311036
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