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Published electronically 19 August 2012

NEW HORIZONS

New horizons in the pathogenesis,

assessment and management of movement
disorders
GORDON W. DUNCAN , ALISON J. YARNALL , SARAH MARRINAN , DAVID J. BURN

Institute of Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
Address correspondence to: G. W. Duncan. Tel: (+44) 191 248 1241; Fax: (+44) 191 248 1251. Email: gordon.duncan@
newcastle.ac.uk

Abstract
In this review, we shall outline recent advances in our understanding of the movement disorders which geriatricians encounter in
their clinical practice. Many of these diseases are no longer simply considered disorders of movement: carefully conducted longitu-
dinal studies have shown that concomitant cognitive dysfunction, neuropsychiatric disturbance and behavioural issues are frequent
and exert a heavy burden on the individual and their carers. Great progress has been made in understanding the molecular and cel-
lular processes that drive the pathological changes in these conditions, as have advances in neuroimaging and preclinical drug dis-
covery programmes. Unfortunately, this is yet to translate into disease-modifying therapies for these progressive disorders.
Advances have been also made in non-pharmacological interventions such as tailored physiotherapy and speech therapy pro-
grammes. The important contribution of palliative care has been recognised and increasingly incorporated into the multidisciplin-
ary approach. The UK is at the forefront of research into these conditions and geriatricians are well placed to contribute to
research through recruiting patients to observational studies or therapeutic trials, particularly with the support of agencies such as
the National Institute for Health ResearchDementias & Neurodegenerative Diseases Research Network (NIHR-DeNDRoN).

Keywords: movement disorders, Parkinsons disease, progressive supranuclear palsy, dementia with Lewy bodies, multiple
system atrophy

Introduction abnormal protein handling and oxidative stress with subse-

In this New Horizons article, we will focus on the move-
ment disorders which geriatricians encounter in routine clin-
ical practice. We will outline recent advances in the clinic and
laboratory and how these are translating into better under-
standing of the pathological processes driving these condi-
tions, improved diagnostic accuracy and, ultimately, paving
the way for the development of disease-modifying therapies.
Degenerative movement disorders
No longer considered purely disorders of movement,
many patients will have co-existent cognitive impairments
and neuropsychiatric disturbances which are equally trouble-
some for them and their carers. These degenerative protei-
nopathies, which are outlined in Table 1, are characterised by
quent cell toxicity and death. Parkinsons disease (PD), de-
mentia with Lewy bodies (DLB) and multiple system atrophy
(MSA) are synucleinopathies, whereas progressive supra-
nuclear palsy (PSP), corticobasal degeneration (CBD) and
some forms of frontotemporal lobe degeneration are driven
by tau pathology. The clinical features are the manifestation
of degeneration in select neuronal populations inuenced by
the distribution of pathology, the proteinopathy driving the
disease and any co-existent pathological processes.
Synucleinopathies
Parkinsons disease
PD is the second most common neurodegenerative dis-
order after Alzheimers disease [1]. The pathological hallmark

2

Table 1. Classification of degenerative movement disorders
according to protein aggregation
Disease Phenotypic variants and clinical
presentations
........................................
Synucleinopathy Parkinsons Early or young-onset
disease Tremor-dominant
Non-tremor dominant/
Postural-instability and gait
difficulty
Rapid disease progression without
dementia
Dementia with Dementia precedes parkinsonism or
Lewy bodies occurs within one year of
parkinsonism onset
Multiple system MSA-Cerebellar variant
atrophy MSA-Parkinsonian variant
Pure Autonomic Failure
Tauopathy Progressive PSP-Richardson syndrome
supranuclear PSP-Parkinsonism
palsy Pure akinesia with gait freezing
Corticobasal Corticobasal syndrome
degeneration PSP-like syndrome
Progressive non-fluent aphasia
Behavioural variant frontotemporal
degeneration
Picks disease Behavioural variant frontotemporal
degeneration
Semantic dementia
Progressive non-fluent aphasia
of PD is degeneration of the dopaminergic neurons within
the substantia nigra pars compacta. Driven by the deposition
of insoluble phosphorylated -synuclein-containing inclu-
sions within the neuronal cytoplasm as Lewy bodies, or
axons as Lewy neurites, these lesions are found throughout
the central and autonomic nervous systems and become
more widespread with disease progression [2]. Animal and
cellular models have conrmed that mitochondrial dysfunc-
tion, abnormal protein aggregation and oxidative stress are
implicated in the pathogenesis of PD, but whether Lewy
pathology is directly cytotoxic or represents a failed response
by the cell to conne and eliminate cytotoxic proteins
remains unclear [3].
The incidence of PD increases with age [1], and an
older age at onset is strongly associated with faster disease
progression [4]. Accounting for only a small proportion of
all cases, monogenetic forms predominate in those with
young-onset PD and at least eight loci of importance have
been identied with Genome Wide Association Studies [5].
Within the general population, a positive family history may
be an important risk factor and mutations in the
leucine-rich repeat kinase 2 gene (designated PARK 8) are
found in 12% of European patients with idiopathic PD
[6]. Some mutations are associated with certain clinical fea-
tures; the H1 haplotype of the microtubule-associated
protein tau gene confers an increased risk of dementia [7].
The UK-wide Tracking Parkinsons Study aims to recruit
New Horizons in the pathogenesis
2500 patients with new and young-onset PD to further
dene the importance of genetic factors in the development
and progression of PD. Environmental factors such as sol-
vents containing trichloroethylene [8] and pesticides [9]
have been linked to PD and require further evaluation.
Clinical advances
The clinical features of PD encompass motor abnormal-
ities, cognitive impairments, autonomic dysfunction and
neuropsychiatric disturbances. Recent research has focused
on motor phenotype classication and its correlation with
pathology and patterns of disease progression. Four distinct
clinical phenotypes have been described and are outlined in
Table 1. Each is associated with a different disease trajec-
tory: those with younger onset or tremor-dominant presen-
tations appear to have a longer time interval to developing
falls and dementia [10]. Patients with postural instability and
gait difculty typically develop falls and dementia sooner
[11], however, these patients are often older and have more
extensive cortical LB deposition [10].
Non-motor symptoms (NMS) are important predictors
of the quality of life [12] and approximately half of NMS
are not reported or recorded [13]. Using the 30-point NMS
screening questionnaire (NMSQuest) in 545 patients across
all stages of PD, Martinez-Martin et al. [14] reported noc-
turia to be the most prevalent NMS. Cognitive, perceptual,
autonomic, sleep and sexual symptoms occurred in over
30% of patients. A recent incidence study highlights that
those with very early PD experienced a greater number of
NMS when compared with age-matched controls, and
those with the postural instability gait disorder subtype of
the disease had a higher burden than those with tremor-
dominant disease (Khoo et al., submitted). The importance
of recognising and managing NMS is emphasised in the
National Institute for Health and Clinical Excellence
Guideline on PD [15]. Many NMS predate the onset of
motor dysfunction by many years [16], offering further
insight into the development of PD and suggesting a pre-
motor phase. LBs have been found in the colonic mucosa
of those with PD up to 5 years prior to the onset of motor
parkinsonism [17], possibly suggesting an intestinal route of
entry with centripetal, or rostral spread. Constipation and
disturbances of sleep, mood and olfaction are common and
collectively may represent a Parkinson at Risk Syndrome,
which is currently the subject of intense study, the ultimate
goal being to identify those at highest risk of developing
PD and allowing the rational targeting of future disease-
modifying strategies.
Cognitive and neuropsychiatric issues
Dementia may ultimately develop in almost 80% of those
with PD [18]. The pattern of cognitive decits in
Parkinson's disease dementia (PDD) is very different from
AD, with visual hallucinations, cognitive uctuations and
visuospatial dysfunction being core features. For research
3
G. W. Duncan et al.
and clinical purposes, DLB is differentiated from PDD by
the 1-year rule [19]: the diagnosis of DLB requires cogni-
tive dysfunction to precede motor symptoms, or occur
within 1year of motor onset. In contrast to the motor man-
ifestations of PD, which reect dopaminergic deciency, de-
mentia is underpinned by a profound cholinergic deciency,
even greater than that seen in AD [20]. A recent Cochrane
Review supports the use of cholinesterase inhibitors, with
rivastigmine having modest benets in global function, cog-
nition, behavioural symptoms and activities of daily living
in those with PDD [21]. For those with early PDD, the
Health Technology Assessment programme funded
UK-based multi-centre MUSTARDD-PD trial will evaluate
the effects of the early institution of donepezil and recruit-
ment will begin shortly.
Subtle cognitive dysfunction or mild cognitive impair-
ment (MCI) occurs in around a quarter of patients and is
reported across all stages of PD [22]. PD-MCI is dened as
a cognitive decline which, although, not normal for age, is
still associated with essentially normal functional activities
[22] and guidance for formal neuropsychological testing is
available [23]. Single domain impairments occur more fre-
quently than multiple domain impairments; attention and
executive impairments are most commonly observed, in
contrast to the general ageing population where amnestic
decits predominate [22]. Two longitudinal studies reported
increased dementia risk in those with PD-MCI [7, 24];
however, further information from large observational
studies is needed to inform the prognostic signicance of
PD-MCI.
Across all stages of PD, major depression is reported in
520% of patients, with a further 130% suffering minor
depressive episodes [25]. The evidence base for treatment is
limited, with trials often small and of short duration.
Selective serotonin reuptake inhibitors are commonly pre-
scribed and a recent placebo-controlled double-blind
randomised controlled trial (RCT) of venlafaxine and par-
oxetine supported the use of both over placebo [26]. There
is some evidence supporting tricyclic anti-depressants such
as nortriptyline and desipramine in PD depression [27, 28],
but their anti-cholinergic properties often make them un-
suitable for this population. The anti-depressant properties
of pramipexole have recently been recognised [29].
Impulse control disorders (ICDs) in those receiving
dopamine agonists (DAs) are an increasingly recognised
phenomenon. In a cross-sectional study of over 3,000
patients with PD [30], 13.6% of patients were identied as
having an ICD, with 3.9% having two or more ICDs.
Compulsive shopping was most prevalent (5.7%), followed
by gambling (5.0%), binge-eating (4.3%) and compulsive
sexual behaviours (3.5%). ICDs were more frequent in
those prescribed a DA compared with other anti-
parkinsonian medications, although it should be noted that
this study consisted of subjects aged under 75, and there-
fore the applicability to older patients may be limited.
Predominately associated with DA use, ICDs have been
reported in patients receiving levodopa [31] and following
4
deep brain stimulation (DBS) [32]. Risk factors for the de-
velopment of an ICD include male sex, younger age and a
history of gambling or depression, and these should be
sought prior to the initiation of DAs and behaviours sug-
gestive of an ICD should be enquired about regularly.
New treatments for PD
In general, the drug development pipeline for PD is relatively
sparse, and almost 50 years after their introduction, L-dopa
preparations remain the most effective form of oral therapy.
Stem cell and gene transfer strategies have thus far proved dis-
appointing. There is a need for better treatments to address
not only the dopaminergic decits, but also the other neuro-
transmitter derangements that occur within the cholinergic,
serotonergic and noradrenergic systems. Table 2 shows some
of the drugs currently being trialled for PD in Europe and
North America. Disease-modifying drugs that slow the rate
of dopaminergic nigral degeneration would simplify the man-
agement of motor problems; likewise slowing the onset of de-
mentia and non-motor features would signicantly enhance
the quality of life for the individual and their carer.
DBS of the subthalamic nucleus (STN) is an established
surgical option [33]. Key to its success is careful lead place-
ment and patient selection: Patients should be under 70
with L-dopa responsive disease and no signicant neuro-
psychiatric or cognitive disturbance, which unfortunately
excludes a signicant proportion of the population seen by
geriatricians. STN stimulation has little impact upon gait
dysfunction, axial symptoms and falls. Undergoing pro-
found degeneration in PD, the pedunculopontine nucleus
(PPN) provides signicant cholinergic input to the basal
ganglia and cortex [34] and may play an important role in
posture and gait. A recent double-blind RCT [35] of unilat-
eral PPN stimulation demonstrated benet in terms of re-
ducing falls, but not the overall UPDRS score; for this to
be achieved, bilateral stimulation of the PPN and subthala-
mic region may be required [36].
Non-drug treatments
Trials of multidisciplinary rehabilitation and exercise are
underway in the UK and Holland. Input from PD specialist
nurses improves patients sense of well-being at no add-
itional cost [37]. Speech and language therapy in the assess-
ment and management of dysphagia is well-established, for
quiet speech and dysphonia the Lee Silverman Voice
Treatment may be benecial [38]. Evidence is growing for
the role of physiotherapy, which may be benecial in im-
proving gait, freezing and falls, but it is important to note
that different strategies are required for different disease
stages and experienced physiotherapists are essential [39].
Dementia with Lewy bodies
Dementia with Lewy bodies is characterised by uctuating im-
pairment of cognition, visual hallucinations and parkinsonism
 New Horizons in the pathogenesis

Table 2. Summary of clinical trials currently testing new drugs for Parkinsons disease in Europe and North America
Drug Action Trial name Phase Comments
....................................................................................
Disease-modifying Creatine Supports mitochondrial function NET-PD III Measures of disease progression over 5
NCT00449865 years
Due to report in May 2015
Inosine Higher serum urate levels are associated SURE-PD II Safety and tolerability study
with slower progression of PD. Inosine NCT00833690 Will measure CSF urate levels in patients
is an urate precursor that raises urate with early PD
levels in blood and CSF
Israpadine CR Calcium antagonist STEADY-PD II Safety and tolerability study
NCT00909545 UPDRS measure of disease progression
N-acetylcysteine Reduces oxidative stress as a free radical NCT01470027 II Measures of glutathione activity and
scavenger clinical measures
Deferiprone An iron chelator that has been shown to NCT01539837 II Safety and tolerability study
reduce iron deposition in Friedreich MRI measures of SN iron accumulation
ataxia patients. Excess iron deposition is
implicated in SN toxicity
Pioglitazone PPAR-gamma agonist that slows disease NCT01280123 II Patients with early PD being recruited to
progression in rats and increases striatal this safety and tolerability study
dopamine levels
AAV2-Neururin Neurotrophic growth factor that is directly NCT00985517 I/II Change from baseline UPDRS III in OFF
(CERE-120) injected into the SN and putamen state
Cogane Oral neurotrophic factor modulator NCT01060878 II Change from baseline in UPDRS II and
(PYM-50028) III in those with early and untreated
PD
Early Motor IPX066 Extended-release oral formulation of NCT01096186 III Open label extension, to APEX-PD
carbidopa and levodopa which showed modest improvement in
UPDRS in those with early PD
Side-effects included nausea and vomiting
Safinamide MAOB inhibitor, dopamine reuptake MOTION III Extension study measuring whether
inhibitor, sodium channel antagonist and NCT01028586 safinamide delays the need to initiation
glutamate release inhibitor of dopaminergic therapy in early PD
patients
Preladenant Adenosine A2 receptor antagonist NCT01155479 III Safety and tolerability study
Change from baseline in UPDRS
Advanced PD AFQ-056 Metabotropic glutamate receptor 5 NCT01491932 II Open label extension phase
antagonist (immediate release) Double blind-phase showed significant
benefit in the primary outcome AIMS
scores

AFQ-056 Metabotropic glutamate receptor 5 NCT01491529 II Safety and efficacy study

antagonist (modified release)
IPX066 Extended-release oral formulation of
carbidopa and levodopa
BIA9-1067 Long-acting COMT inhibitor
Preladenant Adenosine A2 receptor antagonist
Safinamide MAOB inhibitor, dopamine reuptake
inhibitor, sodium channel antagonist and
glutamate release inhibitor
Change from the baseline in the
dyskinesia score in those with
dyskinesia
ADVANCE-PD III Open label extension phase recording
changes in UPDRS and motor
fluctuations based on home diaries.
Earlier phase showed 1.1 h
improvement in ON time without
troublesome dyskinesia compared with
immediate release levodopa
BIPARK2 III Aims to show reduced OFF time
NCT01568073 compared with entacapone or placebo
NCT01155466 III Mean reduction in OFF time
SETTLE III Some increase in ON time increase at 24
NCT00627640 weeks: 50 mg versus placebo 0.59 h (P
= 0.008), 100 mg versus placebo 0.63
h (P = 0.005).
Safety and tolerability measures also

Continued

5
G. W. Duncan et al.

Table 2. Continued
Drug Action Trial name Phase Comments
....................................................................................
XP-21279 Sustained-release formulation levodopa NCT01171313 II Earlier study showed less variability in
pro-drug. Allows more time for L-dopa concentrations than IR
transport across the GI tract carbidopa and levodopa. 60% had
>30% reduction in mean daily OFF
time. Mean time to ON after 1st
morning dose was similar
SYN115 Adenosine A2 receptor antagonist NCT01283594 II/III Change from the baseline in mean OFF
time without troublesome dyskinesia
Nicotine Transdermal nicotine NICOPARK2 II Measuring change in UPDRS in the OFF
NCT00873392 state
Due to report in 2014
AAV-hAADC-2 Gene coding for the enzyme that converts NCT00229736 II Safety study in those with mid-to-late
L-dopa to dopamine (AADC) is inserted stage PD
into a non-pathogenic virus and injected
into the striatum
ProSavin Intraputaminal injection of enzymes NCT00627588 I/II Safety and tolerability study
required for dopamine synthesis
Gait and balance Rivastigmine Acetylcholinesterase inhibitor ReSPonD II Recruiting patients with PD who have
ISRCTN19880883 fallen
Will measure gait variability and other
tasks
Donepezil Acetylcholinesterase inhibitor NCT01521117 IV Measuring changes in balance and walking
Varenicline Nicotinic receptor agonist. Improved Chantix-PD II Change in Berg Balance scale,
imbalance in initial studies in patients NCT01341080 MDS-UPDRS, mood and cognitive
with inherited spinocerebellar ataxia tests
Non-motor Droxidopa Noradrenaline precursor for neurogenic NCT01176240 III Mean change in the Orthostatic
orthostatic hypotension Hypotension Questionnaire composite
score
Lubiprostone Prostaglandin E1 derivative for NCT00849784 IV Measures of change in bowel movement
constipation frequency
Solifenacin Muscarinic receptor antagonist URGE-PD IV Reduction in daily number of micturitions
NCT01018264
Neuropsychiatric Pimavanserin 5HT2A receptor antagonist NCT01518309 III Safety and efficacy studies for the
NCT00550238 treatment of PD psychosis. High
NCT01174004 placebo response with no benefit of
pimavanserin. Trends towards
improvement of psychosis without
impairing mobility
Naltrexone Long-acting opioid receptor antagonist NCT01052831 IV For those with ICDs due to DA therapy,
improvement will be measured by the
global impression of change
Dementia Rivastigmine Acetylcholinesterase inhibitor NCT01519271 IV Due to report in 2014
Recruiting patients with mild cognitive
impairment

Donepezil Acetylcholinesterase inhibitor MUSTARDD-PD III Twenty-two sites across UK aim to recruit
NCT01014858 500 patients with early PD dementia

[19]. Pathologically, there is extensive cortical and neocor-
tical LB deposition which correlates with the severity of
cognitive decline [40] as well as basal forebrain cholinergic
neuronal loss, neurobrillary tangles and deposition of
-amyloid, the latter occurring more often in DLB than
PDD. Differentiation from AD in its early stages can be
challenging and 123I-FP-CIT SPECT imaging may be
helpful [41]. Symptomatic treatment remains limited to rivas-
tigmine [42] or donepezil, which improves both cognition
and behavioural features [43]. Most recently memantine has
been shown to improve some neuropsychiatric features [44].
Multiple system atrophy
MSA manifests as severe autonomic dysfunction with cere-
bellar features (MSA-C), poorly levodopa-responsive par-
kinsonism (MSA-P) or both [45]. The pathological hallmark
is the presence of -synuclein containing glial cytoplasmic

6

inclusions in the central nervous system (CNS) [46]. While
most cases are sporadic, polymorphisms in the SNCA gene
have been identied, adding to our understanding of the
pathogenesis [47]. To date, no treatments have been shown
to slow the disease progression or improve survival.
Riluzole, which prolongs survival in motor neuron disease
(MND), did not improve survival in MSA patients in the
Neuroprotection and Natural History in Parkinson Plus
Syndromes study [48]. A trial of rasagiline in patients with
MSA-P is due to fully report later in 2012 but did not dem-
onstrate efcacy. Potential disease-modifying therapies that
have shown early promise in mice models include erythro-
poietin [49] and rifampicin [50]; the later reduces
-synuclein bril formation and a human trial is underway.
Tauopathies
Tauopathies are characterised by the accumulation of hyper-
phosphorylated tau protein within neurons and glial cells in
the CNS. Normally, tau is a soluble microtubule-associated
protein found within the neuron: in the disease state the ab-
normally insoluble tau forms brillar structures of aggregated,
hyperphosphorylated and ubiquinated tau with subsequent
cellular toxicity. The result is a range of heterogeneous clinical
syndromes with varying degrees of parkinsonism and
dementiaparticularly with frontal lobe involvement or an
MND-like appearance [51].
Progressive supranuclear palsy
Progressive supranuclear palsy is the most common tauopa-
thy and is characterised by abnormal deposition of four-
repeat tau brillary tangles in neurons and glial cells within
the midbrain, pallidum, thalamus and STN [51]. The classic
Steele-Richardson syndrome typically presents in patients
over 40 years of age with akinetic rigidity, early falls (often
backwards) and supranuclear vertical gaze palsy or slowing
of saccades. Other features include frontalis muscle hyper-
activity giving the patient a startled expression, and a dee-
pened voice. Neuropsychiatric disturbances such as apathy,
change in social behaviour and aggression are prominent.
Early impairments of cognition manifest as reduced verbal
uency, inexibility of thought and impaired ability to recog-
nise emotions [52]. Dementia is almost universal with disease
progression. In contrast to the synucleinopathies, hallucina-
tions, autonomic dysfunction and sleep disturbance are rare.
PSP is relentlessly progressive, with death occurring after a
mean of 7 years. More recently, a PSP variant designated
PSP-Parkinson (PSP-P) has been described with clinical fea-
tures similar to PD: gaze palsy is less prominent; bradykinesia,
rigidity and tremor are more unilateral and cognition is pre-
served for longer [53], these patients may respond to L-dopa
and the mean survival is longer. Pure akinesia with gait freez-
ing is another uncommon phenotypic variant of PSP.
Studies of cholinesterase inhibitors [54], gabapentin [55]
and riluzole [48] have been disappointing. Disease-modifying
New Horizons in the pathogenesis
strategies are being developed, which aim to reduce tau de-
position via inhibition of tau hyperphosphorylation and ag-
gregation. Glycogen synthase kinase-3 (GSK-3) is critical for
tau hyperphosphorylation, but trials of GSK-3-inhibiting
drugs, including lithium and Tideglusib have been disappoint-
ing. A further approach is to stabilise the neuronal cytoskel-
eton through enhancing the synthesis of Activity-Dependent
Neuroprotective Protein with nasal davenutide (Allon
Therapeutics) and trials are underway at present. Coenzyme
Q-10, which supports mitochondrial function, showed
promise in a phase II trial and a further trial is ongoing. A
phase III trial of rasagiline is currently recruiting participants.
Corticobasal degeneration
Diagnosis of CBD is challenging: it is rare, and has a
variety of presentations. It may present with the classical
features of corticobasal syndrome (CBS) including limb
dystonia, unilateral limb apraxia, action myoclonus or cor-
tical sensory loss; or with a more PSP-like variant with
aphasia or behavioural change [56, 57]. CBS is a clinical
phenotypic descriptor which may be the manifestation of
a range of different pathologies including tau, Alzheimers
disease pathology, LBs or frontotemporal lobar degener-
ation [57]. Pathological four-repeat tau accumulation is
common to the CBD and PSP and may be present in up
to half of cases of CBS [57]. Treatment is supportive; rivas-
tigmine may improve neuropsychiatric features but with no
impact upon cognition [58], and L-dopa is not helpful.
Other movement disorders
Huntingtons disease (HD) is an autosomal dominant
progressive neurodegenerative disease caused by a
cytosine-adenine-guanine (CAG) trinucleotide repeat expan-
sion in the Huntington gene on chromosome 4 [59] with
severe neuronal loss in the putamen and caudate. The
disease shows anticipation and the age of onset correlates in-
versely with the number of trinucleotide repeats. The clinical
features encompass chorea, dystonia, cognitive, neuropsychi-
atric and metabolic disturbances and may develop between
the ages of 1 and 80 years. Current treatment strategies are
unsatisfactory and include the use of antidepressants and
antipsychotics. Trials of striatal foetal implants are underway,
as are searches for neuroprotective treatments including co-
enzyme Q10. DBS has been used for disabling chorea in
younger patients but experience is limited [60]. North
American and European studies are ongoing in the search
for reliable biomarkers for those with pre-manifest HD.
Essential tremor
Essential tremor has a prevalence of 0.40.9% across all
age groups, rising to 4.6% in those over 65-year-old [61].
No longer labelled as benign, the tremor often progresses
and may be associated with neuropsychiatric, motor and
7
G. W. Duncan et al.
functional co-morbidities [62]. Inherited in an autosomal
dominant manner with reduced penetrance, no convincing
loci have been identied despite exhaustive study, possibly due
to considerable heterogeneity within the patient population
and confounding factors such as age and co-morbid disease.
Pathologically, there may be a loss of cerebellar Purkinje cells,
particularly those expressing GABAA and GABAB receptors
in the dentate nucleus of the cerebellum; brain stem LB de-
position has being reported in some studies also [63].
Propanonlol is established as the rst-line therapy, but up to
half of patients fail to respond [64]. Gabapentin and topira-
mate are the second-line and may work via gamma-aminobu-
tyric acid receptor activation. Refractory cases may be
considered for DBS of the ventralis intermedius nucleus of
the thalamus, often with good results.
Dystonic tremor
This diagnosis has emerged with the increased use of dopa-
mine imaging in therapeutic trials where a misdiagnosis rate of
up to 15% was noted after imaging [65]. Labelled as scans
without evidence of dopaminergic decit (SWEDDS), many
of these patients demonstrated mild dystonic posturing and
were thus considered to have dystonic tremor. The tremor is
usually an atypical jerky rest tremor that is generally unilateral,
may be focal and may display a geste antagoniste (sensory trick
that reduces tremor) [66]. Available oral treatments are unsat-
isfactory, but botulinum toxin injection to focal muscle
groups has been tried with some success.
Horizon scanning
The UK is at the forefront of movement disorder research
and geriatricians are well placed to participate in this.
Within England, the topic-specic NIHR-Dementias &
Neurodegenerative Diseases Research Network (NIHR-
DeNDRoN) has a role in facilitating projects studying PD.
Parkinsons UK is a major funder of PD research in add-
ition to providing education and support for patients and
carers. Success in developing disease-modifying treatments
will require the following: a better understanding of the
mechanisms that underlie neuronal cell toxicity and death;
the development of animal models that accurately reect
disease progression and which may be used for drug dis-
covery programmes; and the validation of biomarkers
which not only permit earlier diagnosis, but also measure
disease progression and response to disease-modifying
therapy. Such biomarkers are likely to be drawn from a
multimodal panel of neuroimaging, blood and cerebrospinal
uid markers.
Advance care planning and palliative care
The relentless progression of most neurodegenerative
movement disorders, high symptom burden and paucity of
disease-modifying treatments make the requirement for a
8
palliative approach essential. The legal framework for
advance care planning (ACP) was provided by the Mental
Capacity Act 2005 [67] and discussions regarding ACP can
be tailored to the patient and their family with regard to
their disease type and stage. Common issues include pre-
ferred place of care, antibiotic use for pulmonary infections
and the use or withdrawal of articial nutrition. Palliative
care physicians are increasingly involved in the care of
patients with advanced PD and other neurodegenerative dis-
eases; unfortunately those with advanced PD are currently
more likely to die in hospital than in a hospice or at home.
Conclusion
Tremendous advances have been made in the characterisa-
tion of the clinical features and underlying cellular mechan-
isms that underpin the movement disorders seen in older
people. These advances have yet to translate into disease-
modifying therapies, which will revolutionise the care these
patients and are currently the focus of intense research efforts.
Acknowledgements
This work was also supported by the UK NIHR
Biomedical Research Centre for Ageing and Age-related
disease award to the Newcastle upon Tyne Hospitals NHS
Foundation Trust.
Conflicts of interest
None declared.
Funding
G.W.D. is supported by a grant from the Newcastle
University Lockhart Parkinson's Disease Fund. He has
received educational grants from UCB and Abbott for
attending conferences. A.J.Y. is supported by grants from
the Newcastle University Lockhart Parkinsons Disease
Fund and MJ Fox Foundation. She has received funds
from Teva-Lundbeck and UCB for attending conferences
S.M. is funded by grants from Parkinsons UK, GSK and
MJ Fox Foundation. She has received funds from UCB
for attending conferences. D.J.B. has received grants from
NIHR, Wellcome Trust, GlaxoSmithKline Ltd, Parkinsons
UK, and Michael J Fox Foundation. He has received hon-
oraria from Teva-Lundbeck and UCB in the past two years
and acted as consultant for GSK and Archimedes.
References
1. Nussbaum RL, Ellis CE. Alzheimers disease and Parkinsons
disease. N Engl J Med 2003; 348: 135664.
2. Braak H, Ghebremedhin E, Rub U et al. Stages in the devel-
opment of Parkinsons disease-related pathology. Cell Tissue
Res 2004; 318: 12134.

3. Jellinger KA. Neuropathology of sporadic Parkinsons
disease: evaluation and changes of concepts. Mov Disord
2012; 27: 830.
4. Post B, Merkus MP, de Haan RJ et al. Prognostic factors for
the progression of Parkinsons disease: a systematic review.
Mov Disord 2007; 22: 183951.
5. Gasser T, Hardy J, Mizuno Y. Milestones in PD genetics.
Mov Disord 2011; 26: 10428.
6. Gilks WP, Abou-Sleiman PM, Gandhi S et al. A common
LRRK2 mutation in idiopathic Parkinsons disease. Lancet
2005; 365: 4156.
7. Williams-Gray CH, Evans JR, Goris A et al. The distinct cog-
nitive syndromes of Parkinsons disease: 5 year follow-up of
the CamPaIGN cohort. Brain 2009; 132: 295869.
8. Goldman SM, Quinlan PJ, Ross GW et al. Solvent exposures
and Parkinson disease risk in twins. Ann Neurol 2012; 71:
77684.
9. Wang A, Costello S, Cockburn M et al. Parkinsons disease
risk from ambient exposure to pesticides. Eur J Epidemiol
2011; 26: 54755.
10. Selikhova M, Williams DR, Kempster PA et al. A clinico-
pathological study of subtypes in Parkinsons disease. Brain
2009; 132: 294757.
11. Burn DJ, Rowan EN, Allan LM et al. Motor subtype and cog-
nitive decline in Parkinsons disease, Parkinsons disease with
dementia, and dementia with Lewy bodies. J Neurol
Neurosurg Psychiatry 2006; 77: 5859.
12. Schrag A. What contributes to quality of life in patients with
Parkinsons disease? J Neurol Neurosurg Psychiatry 2000; 69:
30812.
13. Chaudhuri KR, Prieto-Jurcynska C, Naidu Y et al. The nonde-
claration of nonmotor symptoms of Parkinsons disease to
health care professionals: an international study using the non-
motor symptoms questionnaire. Mov Disord 2010; 25: 7049.
14. Martinez-Martin P, Schapira AHV, Stocchi F et al. Prevalence
of nonmotor symptoms in Parkinsons disease in an inter-
national setting; study using nonmotor symptoms question-
naire in 545 patients. Mov Disord 2007; 22: 16239.
15. National Institute for Health and Clinical Excellence. CG35
Parkinsons disease: Diagnosis and management in primary
and secondary care. 2006; Available at: www.nice.org.uk/
CG035 (accessed 20 February 2012).
16. Gaig C, Tolosa E. When does Parkinsons disease begin?
Mov Disord 2009; 24(Suppl 2): S65664.
17. Shannon KM, Keshavarzian A, Dodiya HB, Jakate S,
Kordower JH. Is alpha-synuclein in the colon a biomarker
for premotor Parkinsons Disease? Evidence from 3 cases.
Mov Disord 2012; 27: 7169.
18. Hely MA, Reid WG, Adena MA et al. The Sydney multicenter
study of Parkinsons disease: the inevitability of dementia at
20 years. Mov Disord 2008; 23: 83744.
19. McKeith IG, Dickson DW, Lowe J et al. Diagnosis and man-
agement of dementia with Lewy bodies: third report of the
DLB Consortium. Neurology 2005; 65: 186372.
20. Bohnen NI, Kaufer DI, Ivanco LS et al. Cortical cholinergic
function is more severely affected in parkinsonian dementia
than in Alzheimer disease: an in vivo positron emission
tomographic study. Arch Neurol 2003; 60: 17458.
21. Rolinski M, Fox C, Maidment I et al Cholinesterase inhibitors
for dementia with Lewy bodies, Parkinsons disease dementia
and cognitive impairment in Parkinsons disease. Cochrane
Database Syst Rev 2012; 3: CD006504.
New Horizons in the pathogenesis
22. Litvan I, Aarsland D, Adler CH et al. MDS task force on
mild cognitive impairment in Parkinsons disease: critical
review of PD-MCI. Mov Disord 2011; 26: 181424.
23. Litvan I, Goldman JG, Troster AI et al. Diagnostic criteria
for mild cognitive impairment in Parkinsons disease:
Movement Disorder Society Task Force guidelines. Mov
Disord 2012; 27: 34956.
24. Janvin CC, Larsen JP, Aarsland D et al. Subtypes of mild cog-
nitive impairment in Parkinsons disease: progression to de-
mentia. Mov Disord 2006; 21: 13439.
25. Reijnders JS, Ehrt U, Weber WE et al. A systematic review of
prevalence studies of depression in Parkinsons disease. Mov
Disord 2008; 23: 1839.
26. Richard IH, McDermott MP, Kurlan R et al. A randomized,
double-blind, placebo-controlled trial of antidepressants in
Parkinson disease. Neurology 2012; 78: 122936.
27. Devos D, Dujardin K, Poirot I et al. Comparison of desipra-
mine and citalopram treatments for depression in Parkinsons
disease: a double-blind, randomized, placebo-controlled
study. Mov Disord 2008; 23: 8507.
28. Menza M, Dobkin RD, Marin H et al. A controlled trial of
antidepressants in patients with Parkinson disease and de-
pression. Neurology 2009; 72: 88692.
29. Barone P, Poewe W, Albrecht S et al. Pramipexole for the
treatment of depressive symptoms in patients with
Parkinsons disease: a randomised, double-blind, placebo-
controlled trial. Lancet Neurol 2010; 9: 57380.
30. Weintraub D, Koester J, Potenza MN et al. Impulse control
disorders in Parkinson disease: a cross-sectional study of
3090 patients. Arch Neurol 2010; 67: 58995.
31. Molina JA, Sainz-Artiga MJ, Fraile A et al. Pathologic gam-
bling in Parkinsons disease: a behavioral manifestation of
pharmacologic treatment? Mov Disord 2000; 15: 86972.
32. Smeding HM, Goudriaan AE, Foncke EM et al. Pathological gam-
bling after bilateral subthalamic nucleus stimulation in Parkinson
disease. J Neurol Neurosurg Psychiatry 2007; 78: 5179.
33. Bronstein JM, Tagliati M, Alterman RL et al Deep brain
stimulation for Parkinson disease: an expert consensus and
review of key issues. Arch Neurol 2011; 68: 165.
34. Pahapill PA, Lozano AM. The pedunculopontine nucleus
and Parkinsons disease. Brain 2000; 123: 176783.
35. Moro E, Hamani C, Poon YY et al. Unilateral pedunculopon-
tine stimulation improves falls in Parkinsons disease. Brain
2010; 133: 21524.
36. Khan S, Javed S, Mooney L et al. Clinical outcomes from bi-
lateral versus unilateral stimulation of the pedunculopontine
nucleus with and without concomitant caudal zona incerta
region stimulation in Parkinsons disease. Br J Neurosurg 2012
Mar 9. [Epub ahead of print] PubMed PMID: 22404735.
37. Jarman B, Hurwitz B, Cook A et al. Effects of community
based nurses specialising in Parkinsons disease on health
outcome and costs: randomised controlled trial. Br Med J
2002; 324: 10725.
38. Ramig LO, Countryman S, OBrien C et al. Intensive speech treat-
ment for patients with Parkinsons disease: short-and long-term
comparison of two techniques. Neurology 1996; 47: 1496504.
39. Rochester L, Nieuwboer A, Lord S. Physiotherapy for
Parkinsons disease: dening evidence within a framework for
intervention. Neurodegener Dis Manag 2011; 1: 5765.
40. Aarsland D, Perry R, Brown A et al. Neuropathology of de-
mentia in Parkinsons disease: a prospective, community-
based study. Ann Neurol 2005; 58: 7736.
9
G. W. Duncan et al.
41. McKeith I, OBrien J, Walker Z et al. Sensitivity and speci-
city of dopamine transporter imaging with 123I-FP-CIT
SPECT in dementia with Lewy bodies: a phase III, multicen-
tre study. Lancet Neurol 2007; 6: 30513.
42. McKeith I, Del Ser T, Spano P et al. Efcacy of rivastigmine
in dementia with Lewy bodies: a randomised, double-blind,
placebo-controlled international study. Lancet 2000; 356:
20316.
43. Mori E, Ikeda M, Kosaka K. Donepezil for dementia with
Lewy bodies: a randomized, placebo-controlled trial. Ann Neurol
2012; 72: 4152.
44. Emre M, Tsolaki M, Bonuccelli U et al. Memantine for
patients with Parkinsons disease dementia or dementia with
Lewy bodies: a randomised, double-blind, placebo-controlled
trial. Lancet Neurol 2010; 9: 96977.
45. Gilman S, Wenning GK, Low PA et al. Second consensus
statement on the diagnosis of multiple system atrophy.
Neurology 2008; 71: 6706.
46. Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions
in the CNS of patients with multiple system atrophy (striato-
nigral degeneration, olivopontocerebellar atrophy and
Shy-Drager syndrome). J Neurol Sci 1989; 94: 79100.
47. Scholz SW, Houlden H, Schulte C et al. SNCA variants are
associated with increased risk for multiple system atrophy.
Ann Neurol 2009; 65: 6104.
48. Bensimon G, Ludolph A, Agid Y et al. Riluzole treatment,
survival and diagnostic criteria in Parkinson plus disorders:
the NNIPPS study. Brain 2009; 132: 15671.
49. Kollensperger M, Krismer F, Pallua A et al. Erythropoietin is
neuroprotective in a transgenic mouse model of multiple
system atrophy. Mov Disord 2011; 26: 50715.
50. Ubhi K, Rockenstein E, Mante M et al. Rifampicin reduces
alpha-synuclein in a transgenic mouse model of multiple
system atrophy. Neuroreport 2008; 19: 12716.
51. Ludolph AC, Kassubek J, Landwehrmeyer BG et al.
Tauopathies with parkinsonism: clinical spectrum, neuro-
pathologic basis, biological markers, and treatment options.
Euro J Neurol 2009; 16: 297309.
52. Ghosh BC, Rowe JB, Calder AJ et al. Emotion recognition
in progressive supranuclear palsy. J Neurol Neurosurg
Psychiatry 2009; 80: 11435.
53. OSullivan SS, Massey LA, Williams DR et al. Clinical out-
comes of progressive supranuclear palsy and multiple system
atrophy. Brain 2008; 131: 136272.
10
54. Litvan I, Phipps M, Pharr VL et al. Randomized placebo-
controlled trial of donepezil in patients with progressive
supranuclear palsy. Neurology 2001; 57: 46773.
55. Poujois A, Vidailhet M, Trocello JM et al. Effect of gabapen-
tin on oculomotor control and parkinsonism in patients with
progressive supranuclear palsy. Eur J Neurol 2007; 14: 10602.
56. Rohrer JD, Lashley T, Schott JM et al. Clinical and neuroana-
tomical signatures of tissue pathology in frontotemporal
lobar degeneration. Brain 2011; 134: 256581.
57. Ling H, OSullivan SS, Holton JL et al. Does corticobasal de-
generation exist? A clinicopathological re-evaluation. Brain
2010; 133: 204557.
58. Liepelt I, Maetzler W, Blaicher HP et al. Treatment of demen-
tia in parkinsonian syndromes with cholinesterase inhibitors.
Demen Geriatr Cogn Disord 2007; 23: 35167.
59. Macdonald ME, Ambrose CM, Duyao MP et al. A novel gene
containing a trinucleotide repeat that is expanded and unstable
on Huntingtons-disease chromosomes. Cell 1993; 72: 97183.
60. Edwards TC, Zrinzo L, Limousin P et al. Deep brain stimulation
in the treatment of chorea. Mov Disord 2012; 27: 35763.
61. Louis ED, Ferreira JJ. How common is the most common
adult movement disorder? Update on the worldwide preva-
lence of essential tremor. Mov Disord 2010; 25: 53441.
62. Louis ED, Okun MS. It is time to remove the benign from the
essential tremor label. Parkinsonism Relat Disord 2011; 17:
51620.
63. Louis ED. Essential tremor: evolving clinicopathological con-
cepts in an era of intensive post-mortem enquiry. Lancet
Neurol 2010; 9: 61322.
64. Zesiewicz TA, Elble RJ, Louis ED et al. Evidence-based
guideline update: treatment of essential tremor Report of the
Quality Standards Subcommittee of the American Academy
of Neurology. Neurology 2011; 77: 17525.
65. Marek K, Seibyl J. Group. PsS. B-CIT scans without evidence
of dopaminergic decit (SWEDD) in the ELLDOPA-CIT and
CALM-CIT study: longterm imaging assessment. Neurology
2003; 60: A298.
66. Elble R, Deuschl G. Milestones in tremor research. Mov
Disord 2011; 26: 1096105.
67. Mental Capacity Act 2005. London: HMSO, 2005. Available
at: http://www.legislation.gov.uk/ukpga/2005/9/contents.
Received 21 May 2012; accepted in revised form 1 June
2012