Narrative review

Updates and advances in the treatment of Parkinson

disease
Michael W Hayes1,2, Victor SC Fung2,3, Thomas E Kimber4,5, John D O’Sullivan6,7

P
arkinson disease (PD) is now conceptualised as a complex Summary
neurodegenerative disorder that can present in diverse
ways with a combination of motor and non-­motor symp- • Parkinson disease (PD) is a complex neurodegenerative disorder
toms. This has resulted in recently published new clinical diag- that can present heterogeneously with a combination of motor
and non-motor symptoms.
nostic criteria1 which incorporate key non-­motor manifestations
including rapid eye movement (REM) sleep behaviour disorder, • α-synuclein, a neuronal protein, can undergo aberrant conforma-
tional change resulting in the intra-neuronal accumulation of toxic
hyposmia and constipation. Biomarkers such as cardiac sympa- oligomers that form Lewy bodies, the pathological hallmark of PD.
thetic denervation as measured by ¹²³I-­metaiodobenzylguanidine
scintigraphy and substantia nigra hyperechogenicity on tran-
• There is evidence that pathological α-synuclein exhibits prion-
like behaviour in its mode of transmission through the nervous
scranial ultrasound are now recognised as supportive criteria. system.
The clinical diagnostic accuracy of PD based on older criteria is • The choice of initial dopaminergic treatments should be individu-
estimated to be about 80%.2 ally tailored but long term outcomes appear to be equivalent.

α-­
synuclein, a neuronal protein widespread in pre-­ synaptic
• There is level A evidence supporting the benefit of three different
device-assisted therapies in treating troublesome motor fluctua-
terminals probably related to vesicle trafficking, can undergo tions and dyskinesias.
aberrant conformational change resulting in the intra-­neuronal • Stem cell transplantation as currently being trialled is predomi-
accumulation of toxic oligomers that form Lewy bodies, the nantly a symptomatic therapy targeting only limited regions of
pathological hallmark of PD. Research interest has recently fo- the brain affected by PD, and will need to be proven to be not
cused on the prion-­like behaviour of α-­synuclein as a potential only as effective but as safe as currently available device-assisted
therapies.
mechanism of spread through the nervous system, probably
starting in the peripheral enteric (gut) nervous system or olfac- • New modes of treatment including active immunisation against
oligomeric α-synuclein and drugs that alter cellular metabolism
tory bulb. A key observation triggering the prion hypothesis was show some promise.
made in post-­mortem studies of PD patients who had been sur-
gically grafted with fetal mesencephalic brain tissue more than
• The inability to effectively treat a range of non-motor, non-dopa-
minergic symptoms remains a major therapeutic challenge.
a decade earlier. A small proportion of these grafted neurons
had developed, in a time-­dependent process, α-­synuclein con-
taining Lewy body pathology, suggesting that there had been
direct transmission from the native PD-­affected neurons to the Early treatment
grafted neuron in a prion-­like manner.3 Subsequently, Lee and
colleagues4 showed that the injection of synthetic α-­synuclein General considerations
into mice resulted in progressive transneuronal spread of Lewy The goals of therapy in PD should be patient-­centred, in order to
pathology in a typical PD distribution. However, there is no evi- maximise quality of life and minimise disability. The first step
dence of inter-­individual transmissibility. in management is the delivery of the diagnosis. Even years later,
Non-­motor symptoms typically pre-­date the onset of the classi- “satisfaction with the explanation of the condition at diagnosis”
cal motor signs of PD by years. About 80% of people who present still has an impact on quality of life,8 but unfortunately many
with later onset REM sleep behaviour disorder will eventually, patients report a poor experience with this process.9 There is no
sometimes after more than a decade, develop motor manifesta- single way of delivering the diagnosis that has been proven to be
tions of a synucleinopathy (PD, Lewy body dementia or multi- optimal, and the approach should be individualised.10
ple system atrophy).5 This observation, coupled with other risk The Global Parkinson’s Disease Survey8 of over 1000 patients
markers such as olfactory loss, has formed the basis of successful found that mood was the greatest determinant of quality of life
attempts to identify prodromal PD, an important step which will in PD, but despite 50% of patients being classified as depressed
allow potential neuroprotective agents to be trialled at an earlierusing the Beck Depression Inventory, only 1% self-­reported de-
stage of the disease.6 These premonitory symptoms of PD pre- pression. Therefore, a high index of suspicion, use of corollary
sumably also offer clues as to the pathogenesis of PD.7 symptoms or screening tools may be required to accurately
Current dopamine-­ related therapeutic strategies remain ef- assess mood. It is also important to address other non-­motor
fective in compensating for dopamine deficiency, but more symptoms such as apathy, fatigue,11and autonomic symptoms
advanced PD is complicated by dysfunction of additional non-­ which also impact on quality of life.
dopaminergic neuronal networks. This narrative review rep-
resents an evidence-­based review of Parkinson disease treatment When to start treatment
derived from systematic reviews, original articles and studies. It Treatment should be started when motor or non-­motor symp-
also includes evidence from expert recommendations, special- toms begin to cause physical or social disability and impair
MJA 2019

12
ist society guidelines (International Parkinson and Movement quality of life. Patients will sometimes hesitate to commence
Disorder Society), as well as personal experience. treatment because of a misguided fear that medications are

1
Concord Repatriation General Hospital, Sydney, NSW. 2 Sydney Medical School, University of Sydney, Sydney, NSW. 3 Westmead Hospital, Sydney, NSW. 4 Royal Adelaide Hospital, Adelaide,
SA. 5 University of Adelaide, Adelaide, SA. 6 Royal Brisbane and Women’s Hospital, Brisbane, QLD. 7 University of Queensland, Brisbane, QLD. [email protected] ▪ doi: 1
10.5694/mja2.50224
 Narrative review
harmful, or that they are only effective for a finite period.13 It is on”). In addition to the development of motor fluctuations, “on”
important to reassure them that there is no evidence to support periods may begin to be associated with involuntary movements
these concerns and, instead, delaying treatment is associated (peak-­dose dyskinesias). Later, dyskinesias may occur at variable
with a progressive decline in quality of life. times in the dosing cycle, during wearing-­off periods as well as
at peak dose (diphasic dyskinesias).
Disease-­modifying therapy
A number of pharmacokinetic factors likely contribute to motor
No treatment has been unequivocally shown to modify the pro- fluctuations. Levodopa may not be reliably delivered to the small
gression of the underlying disease process. A study in de novo intestine, its site of absorption, as a result of delayed gastric emp-
PD showed that patients whose treatment with rasagiline 1 mg tying.21 Additionally, competition from dietary amino acids may
was delayed by 9 months did not experience the same sympto- impede absorption of levodopa from the small intestine (and
matic benefit as those who started treatment immediately, sug- across the blood–brain barrier).22 Data are conflicting on the issue
gesting that earlier treatment may have had a neuroprotective of whether Helicobacter pylori infection can exacerbate motor fluc-
effect.14 However, the 2 mg treatment arms of the same study did tuations by interfering with levodopa absorption.23,24 The use of
not show a difference. Similar study designs with pramipexole15 domperidone and camicinal, another gastroprokinetic drug, en-
and, most recently, levodopa16 also did not show a difference be- hances gastric emptying with more rapid absorption of L-­dopa
tween the immediate and delayed start arms, arguing against a in the proximal small bowel and reduction of “off” time.25
neuroprotective effect of those drugs.
Central factors affecting levodopa pharmacodynamics also
Symptomatic therapy for motor symptoms contribute to motor fluctuations and dyskinesias. Progressively
degenerating nigrostriatal neurons start to lose the capacity to
There is level A evidence (Supporting Information) to support
store dopamine pre-­synaptically. Thus, dopamine is released in
initial treatment with dopamine agonists, levodopa (levodopa–
an increasingly pulsatile fashion, with over-­stimulation of post-­
carbidopa or levodopa–benserazide) and monoamine oxidase
synaptic dopamine receptors (causing peak-­dose dyskinesias)
(MAO)-­B inhibitors (Box 1). Each has potential advantages and
followed by rapid clearance of dopamine (causing offs).26
disadvantages, and treatment should be individualised depend-
ing on the characteristics and needs of the patient, comorbid
Management
non-­motor symptoms, and intercurrent medical illnesses and
medications. The UK-­based PD MED study was a pragmatic A number of strategies can be employed to manage motor
open-­label study comparing patients randomised to initial treat- fluctuations in levodopa-­treated patients with PD. Adjunctive
ment with one of these three different drug classes, followed by dopaminergic therapy such as a dopamine agonist (oral or trans-
routine clinical treatment after randomisation (a large propor- dermal), a catechol-­O-­methyl transferase inhibitor or MAO-­B
tion of patients subsequently crossed treatment arms).17 There inhibitor can be added to the levodopa-­based regimen. In ran-
was a minor reduction (5–10%), in the incidence of dyskinesias in domised controlled trials, each of these three medication classes
those randomised to initial levodopa-­sparing agents at 2–5 years, reduced daily off time by a mean of 1–2 hours relative to pla-
which had narrowed to 3% at 7 years, but otherwise little differ- cebo.27–29 Opicapone, a once-­daily oral catechol-­O-­methyl trans-
ence between the three groups. This provides reassurance that ferase inhibitor, was non-­inferior (at a dose of 50  mg daily) to
in a real-­life setting, there is no absolute right or wrong choice. entacapone in the reduction in daily off time.30 Of the dopamine
agonists, transdermal rotigotine has been shown to improve
early morning motor symptom control.31
Non-­pharmacological therapy
A number of different exercise and physical therapies have been Other strategies to manage motor fluctuations include dividing
trialled to improve walking, balance and falls in PD, including the daily levodopa dose into smaller aliquots administered more
balance, resistance and aerobic exercise, external cueing and frequently.32 High quality evidence on the place of controlled
treadmill walking, movement strategy training, dance (particu- release levodopa formulations is lacking. We recommend that
lar partnered dance) and Tai Chi. Systematic reviews confirm controlled release levodopa preparations be reserved for admin-
that improvements can occur in balance, mobility and muscle istration at bedtime, as their efficacy can be unreliable, possibly
strength.18 Most studies have focused on patients with more due to erratic gastrointestinal absorption.
long-­standing as opposed to early PD, but a recent study of de Safinamide is an α-­aminoamide with several different modes
novo patients showed that high intensity treadmill exercise re- of action, including MAO-­B inhibition and modulation of glu-
sulted in less decline in motor function at 6 months compared tamate release.33 Recent studies with safinamide added to
with usual care.19 Given the established general health and mood levodopa have shown an improvement in on time without exac-
benefits of exercise, it is our practice to recommend a combina- erbation of troublesome dyskinesia, a potential advantage over
tion of moderate aerobic, active balance and resistance exercises other adjunctive dopaminergic therapies.34 Zonisamide, a mixed
to all patients. MAO-­B inhibitor, channel blocker and glutamate release inhibi-
tor, is efficacious in the treatment of wearing-­off symptoms at a
Management of patients with motor fluctuations and dose of 50 mg daily.35
dyskinesias
In addition to adjunctive oral or transdermal dopaminergic ther-
Background apy, intermittent subcutaneous apomorphine injections can be
helpful for patients experiencing troublesome off episodes.36
MJA 2019

After several years of levodopa therapy, patients commonly

experience fluctuations in their motor response (motor fluctua- Immediate release amantadine can help suppress levodopa-­
tions).20 Motor fluctuations may manifest as a decline in motor induced dyskinesias. Recent studies have provided level A
symptoms before the next dose is due (“wearing-­off phenom- evidence for the efficacy of extended release amantadine in re-
enon”, or “end-­of-­dose deterioration”), a delayed response to ducing dyskinesias, an effect achieved at the same time as reduc-
2 a dose (“delayed on”), or even a failure of motor response (“no ing off time.37
 Narrative review

1  Treatment options for early Parkinson disease

Prescribing Level of
Drug class Drugs available in Australia status evidence* Comments

Levodopa Levodopa–carbidopa IR PBS A Most potent anti-­Parkinsonian effect. Maximal therapeu-

tic dose usually tolerated with slow titration. Peripheral
Levodopa–benserazide IR PBS A dopa-­decarboxylase inhibition reduces gastrointestinal
Levodopa–carbidopa CR PBS A tract and peripheral cardiovascular dopaminergic side
effects. Frequent dosing required with advancing disease
Levodopa–benserazide CR PBS A and delayed gastric emptying results in unpredictable
motor fluctuations as levodopa only absorbed from small
intestine. CR preparations should help contract these
problems, but in reality absorption becomes even more
unpredictable, resulting in ongoing motor fluctuations.

Dopamine agonists Pramipexole PBS A Initiating treatment with a dopamine agonist compared
with levodopa will result in an approximate 35% v 50%
Rotigotine PBS A risk of developing dyskinesias after 3–5 years of treat-
Ropinirole TGA A ment. Pramipexole but not rotigotine also has some
antidepressant benefits. Risk of side effects of impulse
control disorder approaches 50% over 5 years; also dan-
ger of excessive daytime somnolence sufficient to cause
sleep attacks and motor vehicle accidents.
Bromocriptine, cabergoline PBS A Ergot dopamine agonists. Similar efficacy to non-­ergot
dopamine agonists. Possibly less somnolence but risk of
impulse control disorders probably similar. Risks of cardiac
valvular, pleuropulmonary and retroperitoneal fibrosis
that may be difficult to diagnose and may require regular
monitoring have led to caution; now rarely used in view of
other therapeutic options available if patients intolerant
of non-­ergot dopamine agonists.

Monoamine oxidase Rasagiline PBS A Rasagiline may have small disease-­modifying effect; all
inhibitors have potentially mild to moderate symptomatic benefit
Safinamide PBS A with occasional mildly affected patients able to maintain
Selegiline PBS A as monotherapy for a while.

Anticholinergics Benzhexol PBS B Used occasionally for control or rest or re-­emergent

tremor unresponsive to dopaminergic therapy at desired
Benztropine PBS B doses; does not treat akinesia; beware of anticholinergic
side effects. Concerns about long term risks of cognitive
impairment.

Catechol-­O-­ Entacopine PBS A Primarily for extending on time when levodopa used ≥ 3
methyltransferase times daily. Multidose options available as carbidopa–lev-
inhibitors odopa–entacapone formulation but may need to reduce
levodopa dose slightly when switching from levodopa
alone.

Other Amantadine PBS A Most useful as add-­on therapy in later disease for treat-
ment of dyskinesias. Can be used in early disease as
alternative to other therapies for mild anti-­Parkinsonian
effect.

CR = controlled release; IR = immediate release; PBS = Pharmaceutical Benefits Scheme; TGA = Therapeutic Goods Administration. * See Supporting Information for explanation of levels of
evidence.◆

dyskinesias, and improve performance of activities of daily liv-

Device-­assisted therapies for motor fluctuations and ing and quality of life. No blinded, randomised trials compar-
dyskinesias ing the efficacy of the three device-­assisted therapies exist. Long
In most patients with PD, motor fluctuations and dyskinesias term adherence to apomorphine infusion may be difficult to
are relatively mild and can be adequately managed by adjust- achieve in some patients.43 However, apomorphine is the least
ment of the oral/transdermal medication regimen. However, for invasive of the three device-­assisted therapies, as well as the
patients experiencing disabling motor fluctuations and dyskine- most straightforward to initiate and discontinue.
sias despite optimised medical therapy (including ≥ 4–5 doses
of levodopa per day), device-­assisted therapies should be consid- Evidence suggests that subthalamic nucleus deep brain stim-
ered (Box 2).38 Level A evidence supports the use of deep brain ulation in selected younger patients with PD (< 60 years) with
MJA 2019

stimulation surgery (targeting either the subthalamic nucleus39 a relatively short (<  3 years) history of motor fluctuations and
or globus pallidus interna40), subcutaneous apomorphine infu- dyskinesias produces a greater improvement in motor function
sion,41 and levodopa–carbidopa intestinal gel infusion via a per- and quality of life compared with optimised medical therapy.44
cutaneous gastrojejunostomy tube42 in such patients. All three The United States Food and Drug Administration has recently
device-­assisted therapies reduce daily off time by several hours approved the use of magnetic resonance imaging-­guided fo-
compared with baseline, increase on time without troublesome cused ultrasound thalamic lesioning for treatment of (unilateral) 3
 Narrative review
noradrenaline reuptake inhibitor venlafaxine in addition to
2  When to refer for consideration of a device-­assisted earlier trials supporting tricyclic antidepressants nortriptyline
therapy38 (level C) and desipramine.53 Adverse effects of antidepressants
■ Motor fluctuations cause disability or reduced quality of life
include orthostatic hypotension and sleep disturbance. Non-­
■ Response to treatment is inconsistent
■ Dyskinesias or motor fluctuations require frequent treatment adjustment motor wearing-­off can manifest as acute anxiety or dysphoria,
without apparent benefit often responsive to dopaminergic medication adjustment.
■ Levodopa required four or more times daily
Neuropsychiatric symptoms
Psychotic symptoms may occur in up to 60% of patients with
tremor-­dominant PD but reliable clinical trial evidence is still
PD; risk factors include advanced age, PD severity and duration,
pending.
comorbid dementia, depression, REM sleep behaviour disorder
Individual patient characteristics (eg, nature of motor symp- and visual disorders.54 Symptoms range from mild illusions to
toms, age, comorbidities) and therapy-­specific risks and adverse frank visual hallucinations and paranoid delusions. Reduction
effects influence the optimal choice of device-­assisted therapy. of dopaminergic drugs is often necessary in conjunction with
These issues are summarised in Box 3 and addressed in greater identifying and treating coexisting delirium. The highly selec-
detail in expert reviews.38,45 Patients requiring consideration of tive serotonin 5-HT2A inverse agonist pimavanserin has been
a device-­assisted therapy should be referred to a neurologist shown to be effective in reducing psychosis in PD (level A) with-
specialising in the management of PD, preferably in a clinic that out worsening motor symptoms,55 but it is not yet registered
offers all three options. with the Therapeutic Goods Administration. Clozapine is also
effective (level B), but its use is limited by haematological and
Non-­motor symptoms cardiac toxicity.53 Quetiapine (level C) is unlikely to aggravate
motor parkinsonism and had similar efficacy to clozapine in
Non-­motor symptoms are increasingly identified in patients at comparator trials, although it was not effective in three ran-
all stages of PD and contribute significantly to morbidity. The domised controlled trials and can cause sedation and hypoten-
topic has recently been reviewed in this journal.46 A patient-­rated sion.56 More conventional antipsychotics including olanzapine
non-­motor symptom questionnaire47 may be helpful in busy and risperidone worsen motor symptoms and can potentially
clinical settings where the focus is often on motor symptoms. trigger parkinsonism–hyperpyrexia syndrome due to dopamine
blockade.
Sleep disturbance Impulse control disorders typically involve compulsive gambling,
Around one-­third of patients with PD report insomnia, excessive buying, sexual behaviour and binge eating, often with serious
daytime somnolence, REM sleep behaviour disturbance or rest- personal, psychosocial and financial consequences. Dopamine ag-
less legs syndrome.46 Recent evidence suggests that the topical onists confer an impulse control disorder risk of around 20% and
dopamine agonist rotigotine improves sleep,48 and that the se- a cumulative risk of around 40% over 5 years. Male sex, younger
lective MAO-­B inhibitor rasagiline reduces fatigue.49 Melatonin age, earlier PD onset, a premorbid impulse control disorder, a per-
or clonazepam may help manage insomnia and REM sleep be- sonal or family history of substance abuse, bipolar disorder and
haviour disorder in some patients, although clinical trials have gambling problems increase the risk of impulse control disorder.57
not been conclusive. Dopaminergic drug dose reduction is often necessary but can be
complicated by motor worsening and dopamine agonist with-
Autonomic dysfunction drawal syndrome characterised by dysphoria and depression.
Orthostatic hypotension is common in PD and is aggravated by Some evidence supports benefit from cognitive behaviour ther-
increased dopamine replacement therapy and reduced oral fluid apy.58 Dopamine dysregulation, hobbyism and punding (repeti-
intake due to dysphagia or self-­restriction to minimise urinary tive stereotypical behaviour) are related problems more common
symptoms. However, treatment of orthostatic hypotension can with shorter acting dopaminergic treatments including levodopa.
aggravate supine hypertension. There is some evidence that All such patients, and preferably family and carers, should be ed-
shorter-­acting drugs like droxidopa, a synthetic noradrenaline ucated about and assessed for impulse control disorders.
precursor,50 and midodrine might be preferable to longer-­acting
pressor agents such as fludrocortisone, especially when there Cognitive impairment
is coexisting supine hypertension.51 Standing blood pressures Cognitive dysfunction is common, increasing with PD duration
should be measured and it may be necessary to prioritise symp- but also occurring earlier in the disease, and is often a major con-
tomatic orthostatic hypotension over sitting or supine hyperten- cern for patients and carers. Rivastigmine remains the only phar-
sion. Urinary dysfunctions, including urgency and nocturia, are macological treatment with level A evidence for management of
among the most prevalent non-­motor symptoms in PD52 but evi- dementia in PD.53 It is only reimbursed on the Pharmaceutical
dence concerning effective therapies is limited. In one randomised Benefits Scheme for Alzheimer disease, although over one-­third
controlled trial, solifenacin reduced incontinence but not the fre- of patients with PD have coexistent Alzheimer pathology and
quency of micturition compared with placebo.52 Constipation is clinical differentiation between the two during life can be dif-
also very common, with limited evidence supporting the use of ficult.59 There is emerging evidence of benefit from exercise and
the osmotic laxative macrogol and, more recently, lubiprostone.53 cognitive rehabilitation to prevent cognitive decline in PD but
Box 4 provides some practical suggestions to manage autonomic more rigorous trial designs and outcomes are required.
MJA 2019

symptoms given the limited clinical trial evidence.

Newer treatment strategies
Mood disturbance
Depression and anxiety remain common but under-­recognised In order to circumvent the contribution of delayed gastric emp-
4 and undertreated causes of significant morbidity in PD. There is tying to motor fluctuations, novel oral formulations or paren-
evidence for the dopamine agonist pramipexole and the selective teral delivery of levodopa have been developed.60 IPX066 is an
 Narrative review

3  Broad indications and considerations for device-­assisted therapies

Levodopa–carbidopa
Deep brain stimulation intestinal gel infusion Subcutaneous apomorphine

Dyskinesias Probable benefit Probable benefit Probable benefit

Medication-­refractory tremor Probable benefit

Mild dementia Probable benefit Possible benefit

Dysarthria/dysphagia Probable benefit Probable benefit

Impulse control disorders Probable benefit Possible benefit

Age > 70 years Possible benefit Probable benefit Probable benefit

Depression Possible benefit Probable benefit

Goal of monotherapy Probable benefit

4  Treatments for autonomic symptoms

Condition Treatment Prescribing status Comment

Orthostatic hypotension Fludrocortisone 0.1–0.3 mg daily PBS

Midodrine 2.5–10 mg daily SAS

Domperidone 10–30 mg daily PBS Caution in older patients with drugs

increasing QT interval

Pyridostigmine 30–90 mg daily PBS restricted

Droxidopa 300–1800 mg daily SAS

Thigh-­high compression stockings

Head-­up tilt in bed 15–25 cm

Urinary dysfunction Oxybutinin 5–15 mg daily PBS Usually limit medication to night-­time

Solifenacin 10–15 mg daily TGA Anticholinergics can worsen constipation

Mirabegron 50–100 mg daily TGA

Tolteridone 2–4 mg daily TGA

Amitriptyline 10–30 mg daily PBS

Nortriptyline 5–25 mg daily PBS restricted

Constipation Macrogol PBS

Stool softeners OTC

Magnesium sulfate OTC

Probiotics OTC

Adequate fluid, fibre and fruit

Erectile dysfunction Sildenafil 25–100 mg PBS restricted

Tadalafil 20 mg PBS restricted

Vardenafil 10–20 mg PBS restricted

Apomorphine 1–6 mg subcutaneous PBS restricted

Sialorrhoea Botulinum toxin (A or B) into parotid glands Off label Some include submandibular glands with
ultrasound guidance

1% topical atropine 1–2 drops sublingual PBS (off label) Can cause confusion

Glycopyrolate 0.4 mg sublingual TGA

◆
MJA 2019

PBS = Pharmaceutical Benefits Scheme; OTC = over the counter; SAS = Special Access Scheme; TGA = Therapeutic Goods Administration.

extended release formulation of levodopa–carbidopa that is mar- effective in improving motor function compared with placebo
keted in the United States for treatment of motor fluctuations in fluctuators and was approved for use by the Food and Drug
and reduced off time by 1.2 hours compared with immediate Administration in December 2018. Subcutaneous forms of levo- 5
release treatment.61 Inhaled levodopa62 has been shown to be dopa are currently being trialled.
 Narrative review
Beyond a purely symptomatic approach to managing PD lies 12-­month period. A rationale for this is that glycation enhances
the goal of neuroprotective or even restorative therapies. The α-­synuclein toxicity via cellular processes and glycation inhibi-
emergence of inducible pluripotent stem cell technology has tors reverse this effect. It has also been proposed that increased
bypassed the ethical issues of transplanting fetal stem cell central (brain) insulin resistance may reduce neuronal survival.67
tissue. Stem cell transplantation as currently being trialled63 Exenatide, a glucagon-­like peptide-1 receptor agonist that can
remains predominantly a symptomatic therapy targeting only cross the blood–brain barrier, resulted in a small motor benefit
limited regions of the brain affected by PD, and will need to be compared with placebo over 48 weeks when measured after a
proven to be not only as effective but as safe as currently avail- 3-­month washout.
able device-­assisted therapies. A rash of commercial stem cell
A rare lysosomal storage disorder, Gaucher disease, has unex-
clinics have largely utilised mesenchymal stem cells injected
pectedly offered insights into the genetic and cellular mecha-
systemically without strict clinical trial protocols. Another re-
nisms of PD. Deficiency of the enzyme glucocerebrosidase due
storative option is delivering glial-­derived neurotrophic factor
to homozygous or compound heterozygous mutations in the
to specific brain regions via a novel delivery system. Recent
glucocerebrosidase gene cause autosomal recessive Gaucher dis-
publications report encouraging but inconclusive results in
ease, while heterozygous mutations have emerged as the most
patients with PD.64
common genetic risk factor for PD.68 Lysosomal glucocerebro-
A further therapeutic approach involves using active and pas- sidase deficiency impairs α-­synuclein clearance, in turn further
sive immunisation techniques. A vaccine (PD01A) that produces reducing glucocerebrosidase activity. Ambroxol, an established
antibodies to oligomeric α-­synuclein has been reported to show drug with mucolytic effects, increases glucocerebrosidase activ-
proof of principle and there are phase I studies utilising mono- ity69 and is currently being trialled (https​://clini​caltr​ials.gov/
clonal antibodies against aggregated α-­synuclein, a form of pas- ct2/show/NCT02​941822) in patients with a heterozygous gluco-
sive immunisation.65 cerebrosidase mutation. These insights into cellular dysfunction
offer a new type of potential treatment, termed substrate reduc-
The massive cost of developing new drugs has led to recent
tion therapies.
interest in repurposing medications previously used in other
areas. An observation that diabetes mellitus may be a modest Competing interests: No relevant disclosures.
risk factor for PD, as well as increasing the rate of progression,66
has resulted in some clinical trial evidence that glucagon-­like Provenance: Commissioned; externally peer reviewed. ■
peptide-1 receptor agonists and dipeptidyl peptidase-­4 inhib-
itors may slightly slow PD symptomatic progression over a © 2019 AMPCo Pty Ltd

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