DOI: 10.
1093/brain/awh198
REVIEW ARTICLE
Biomarkers and Parkinson’s disease
A. W. Michell, S. J. G. Lewis, T. Foltynie and R. A. Barker
Cambridge Centre for Brain Repair, Cambridge, UK
Summary
Biomarkers are characteristics that can be measured as an
indicator of a normal biological process, and they have
special relevance in Parkinson’s disease. Parkinson’s dis-
ease is a chronic neurodegenerative disorder that is difficult
to study, given the site of pathology and because the result-
ant clinical phenotype fluctuates over time. We currently
have no definitive diagnostic test, and thus for the clinician
there is hope that biomarkers will help diagnose sympto-
matic and presymptomatic disease or provide surrogate
Keywords: biomarkers; Parkinson’s disease; diagnosis
Abbreviations: DAT ¼ dopamine transport; MIBG ¼ metaiodobenzylguanidine; MSA ¼ multiple system atrophy;
SPECT ¼ single-photon emission computed tomography
Received October 16, 2003. Revised March 9, 2004. Accepted March 14, 2004. Advanced Access publication June 23, 2004
Introduction
Parkinson’s disease is a common chronic neurodegenerative
disorder in which there is a loss of dopaminergic nigrostriatal
neurons in the substantia nigra pars compacta with evidence of
intracytoplasmic inclusions known as Lewy bodies. The clas-
sical clinical features are of progressive tremor, rigidity and
bradykinesia. However, neuronal loss occurs beyond the dopa-
minergic system, and consequently patients display auto-
nomic, affective and cognitive deficits. Parkinson’s disease
can be difficult to diagnose in its early stages, and may be
mimicked by other diseases, such as essential tremor, multiple
system atrophy (MSA) and progressive supranuclear palsy (see
reviews by Galvin et al., 2001; Burn and Lees, 2002; Poewe and
Wenning, 2002).
Optimization of our treatment of Parkinson’s disease
requires accurate information both about the ongoing disease
process in the brain and its corresponding clinical syndrome.
However, in Parkinson’s disease the key pathology is in the
brainstem, hidden from direct study during life, and this,
coupled to a fluctuating clinical syndrome over time, makes
it difficult to monitor in an unbiased and objective manner.
Biomarkers aim to improve our data collection and
knowledge about both the clinical and pathological
Brain Vol. 127 No. 8 # Guarantors of Brain 2004; all rights reserved
Brain (2004), 127, 1693–1705
Correspondence to: Dr A. W. Michell, Cambridge Centre for
Brain Repair, Forvie Site, Robinson Way, CB2 2PY, UK
E-mail: awm13@cam.ac.uk
end-points to demonstrate clinical efficacy of new treat-
ments, such as neuroprotective therapies, and help stratify
this heterogeneous disease. No biomarker is likely to fulfil
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all these functions, so we need to know how each has been
validated in order to understand their uses and limitations,
and be aware of potential pitfalls. In this review we discuss
the current potential biomarkers for Parkinson’s disease,
highlight the problems with their use, and conclude with a
discussion of future alternatives.
parametersofdisease(seetextbox1foradefinition;Biomarkers
Definitions Working Group, 2001), which is complicated in
Parkinson’s disease by a rather poor correlation between the
underlying pathology and the subsequent clinical phenotype.
This review therefore aims to clarify the understanding of bio-
markers and their relevance to Parkinson’s disease with a
discussion of current candidates and their potential successors.
Why do we need a marker for Parkinson’s
disease?
To improve diagnosis
To many, the most intuitive goal for a biomarker is to help
diagnose disease. For Parkinson’s disease this may be divided
into two separate aims: differentiation of susceptible indivi-
duals from normals before symptoms develop (sensitivity), and
identification of true idiopathic Parkinson’s disease from its
imitators once symptomatic (specificity).
Even in highly specialized centres the sensitivity of the
clinical diagnosis of Parkinson’s disease in symptomatic
patients is only about 91% (Hughes et al., 2002), and it is likely
to be far less in other settings (Rajput et al., 1991; Hughes et al.,
1694 A. W. Michell et al.
Text Box 1 Definitions (from the Biomarkers Definitions
Working Group)
Biomarker (biological marker) A characteristic that is objec-
tively measured and evaluated as an indicator of normal bio-
logical processes, pathogenic processes or pharmacological
responses to a therapeutic intervention.
Surrogate marker A biomarker that is intended to substitute
for a clinical end-point. A surrogate end-point is expected to
predict clinical benefit (or harm or lack of benefit or harm)
based on epidemiological, therapeutic, pathophysiological or
other scientific evidence.
Surrogate markers are a subset of biomarkers.
Clinical end-point A characteristic or variable that reflects how
a patient feels, functions or survives.
Disease-modifying therapy Treatment that affects the under-
lying pathophysiology of disease rather than purely its symp-
toms (although there may be symptom improvement as a result
of these treatments).
For Parkinson’s disease, neuroprotective and neurorestorative
therapies are potential disease-modifying therapies.
1992). Thus it is clear that any way of detecting true idiopathic
Parkinson’s disease and distinguishing it from the numerous
causes of a similar clinical syndrome would be beneficial,
enabling better epidemiology and natural history studies and
allowing cheaper, more powerful clinical trials.
For Parkinson’s disease the need for early presymptomatic
diagnosis is driven by the evolution of putative neuroprotective
agents (Stocchi and Olanow 2003) that would ideally be admin-
istered as soon as the characteristic pathology is detected, given
that
50% reduction in dopaminergic nigral cells is required
before clinical expression (Fearnley and Lees, 1991). It seems
likely that this presymptomatic phase of Parkinson’s disease
lasts
5 years, given recent pathological studies (Fearnley and
Lees, 1991) and imaging data (Morrish et al., 1996a; Marek
et al., 2001). However, patients may develop subtle clinical
correlates corresponding to a prodromal syndrome lasting 4–6
years (Gonera et al., 1997), thus providing an opportunity to
make an early diagnosis before the onset of characteristic
extrapyramidal motor symptoms (Fig. 1).
To monitor disease progression and
demonstrate treatment efficacy
Once a diagnosis of Parkinson’s disease is established, the role
of biomarkers changes. One valuable role is in longitudinal
clinical treatment trials to provide surrogate end-points which,
if adequately validated, can provide a degree of objectivity and
potentially enable a reduction in both the duration of a trial and
the number of patients required for significance. Examples
include the measurement of blood pressure and cholesterol
that have been clearly linked to mortality from myocardial
infarction and stroke in large trials (Scandinavian Simvastatin
Survival Study Group, 1994; Hansson et al., 1998) and are now
accepted end-points for drug licensing. Unfortunately, at pre-
sent no such biomarkers exist for Parkinson’s disease.
Pathological
progression
Pre-diagnostic phase
P Treatment
Pre-symptomatic
C
D
Time
Pathological Non-specific Specific
onset
Symptom onset Diagnosis
Fig. 1 The role of biomarkers in the diagnosis of Parkinson’s
disease. A susceptible person develops Parkinson’s disease as a
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result of their genes and environmental exposure. At some point
after this the pathological process begins, but there are still no
symptoms until
50% of the dopaminergic cells in the
substantia nigra are lost, a process estimated to take
5 years. At
first the symptoms are rather non-specific, with an estimated 4–6
year lag period until the diagnosis of Parkinson’s disease is made
on the basis of the characteristic symptoms that eventually
develop. For different patients the overall rate of disease
progression (slope of the graph) will differ, and is likely also to
alter over time within a single patient (making it non-linear). The
diagnosis and subsequent treatment of patients can be expedited
if patients present earlier with the characteristic phenotype of
disease, and if our clinical diagnostic skills are improved (D).
Alternatively, it may be possible to develop clinical tests that can
positively identify the earlier symptoms that are currently
regarded as non-specific (C). Finally, it seems increasingly
plausible we shall be able to detect the earliest pathological
changes even before symptoms develop, potentially
allowing the use of neuroprotective agents as early as
possible (P).
In established Parkinson’s disease there are two
particular problems for surrogate markers to overcome.
Firstly it is difficult to be sure about the magnitude of
treatment effect by clinical assessment since symptoms
fluctuate over time and the majority of patient assessments
are subjective. Attempts to overcome subjectivity have
included the use of rating scales, such as the Unified
Parkinson’s Disease Rating Scale, which has been shown
to have reasonable interobserver variability, although it
is biased towards assessment of motor deficits (Martinez-
Martin et al., 1994).
The second hurdle is that some putative neuroprotective
agents (for example dopamine agonists, discussed below)
also have symptomatic effects unrelated to their disease-
modifying action. This affects the ability of clinical rating
scales to detect the neuroprotective action even if patients are
assessed after a 12 h washout period, since dopaminergic
stimulation lasts much longer than this (Nutt et al., 2002).
Thus, there is a need for a biomarker that can reliably
detect retarded pathological progression without relying on
symptoms.

What is the marker telling us?
Before we can use biomarkers for Parkinson’s disease, it
is essential to determine exactly what they are measuring,
and therefore what information they can and cannot provide
(Fig. 2). On the one hand, there exists an underlying disease
process, which might be considered to be one of a number of
events, such as Lewy body formation, neuronal degenera-
tion, dopamine depletion and so on. On the other hand, there
are a range of clinical phenotypes caused by this process.
The problem in Parkinson’s disease is that there is poor
clinicopathological correlation, meaning that you cannot
reliably predict clinical phenotype if you know the pathol-
ogy, and vice versa. So, for example, a patient’s symptoms
fluctuate hour by hour, but their pathology presumably does
not. In addition,
10% of people over 60 have incidental
Lewy bodies in their brain, yet only a fraction of these ever
A PD pathology Clinical phenotype Other diseases
B Pathology Clinical Other diseases
Symptomatic
treatment Biomarker
C Pathology Clinical Other diseases
Disease
modifying
treatment
Biomarker
Fig. 2 What does the biomarker tell us about Parkinson’s
disease? (A) In Parkinson’s disease there is a relatively poor
correlation between degeneration of dopaminergic nigral cells
and the clinical phenotype (which can be mimicked by other
diseases). (B) Clinical biomarkers and symptomatic treatments.
Some markers will closely reflect the clinical phenotype and
could help determine the effects of symptomatic treatments (e.g.
levodopa may affect a neurophysiological biomarker that
monitors tremor). These markers will not allow earliest diagnosis
before clinical expression of the disease, but they may assist in
diagnosis before classical symptoms develop, and may help
stratify this heterogeneous disease. To be specific they must not
be abnormal in diseases other than Parkinson’s disease. (C)
Pathological markers and disease modifying treatments. These
biomarkers are primarily designed to reflect the underlying
pathology of disease rather than clinical phenotype, and ideally
would not be affected by purely symptomatic therapy (e.g. the
use of 18F-dopa PET to demonstrate neuroprotection by
dopamine agonists). This type of marker could potentially be
used for very early preclinical disease detection, to monitor
disease progression, or to provide information about disease
stage and prognosis. Note that in both B and C the treatment
ideally should not affect the marker directly.
Biomarkers and Parkinson’s disease 1695
develop symptoms (Fearnley and Lees, 1991; Ben-Shlomo
and Wenning, 1994). Furthermore, as discussed above, our
ability to predict pathology (diagnose) from clinical
phenotype is poor. The result is that a biomarker targeted
to the detection of pathology may well not be able to provide
clinical information, and vice versa.
Of course, in reality markers that are designed to provide
information about pathology can also provide some informa-
tion about clinical symptoms by correlation. For example,
imaging serotonergic function by 11C-WAY100635 PET not
only provides information about the degeneration in median
raphe signalling but also correlates with rest tremor (Doder
et al., 2003). The important point is to appreciate what the
biomarker (in this case PET imaging) was primarily designed
to monitor (pathology here) and what information is acquired
by correlation (clinical phenotype, in particular rest tremor). In
this example the PET scan is not a biomarker for rest tremor, and
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the observed association might be lost in a different population.
What are the problems in using biomarkers in
clinical practice?
Pitfalls when using biomarkers in diagnosis
Biomarkers have a positive predictive value, which provides a
measure of the chance that a patient with a positive result has
the disease. Naturally, we wish to improve the positive
predictive value of a biomarker, but this can only be done
by increasing its specificity (an intrinsic property of the
test that we can not alter) or by an increase in the prevalence
of the disease (perhaps by testing only those at increased risk).
There is a natural tendency for clinicians to combine bio-
markers when faced with a symptomatic patient they suspect
has a disease in whom test results have so far proved negative.
Although tests can be statistically combined, in order for an
additional test to improve diagnostic accuracy it should be
independent of those already in use, which can be difficult
in practice. The use of multiple diagnostic biomarkers will
tend to increase the likelihood of type 1 errors—diagnosing
an unaffected person as having the disease (for a discussion see
Schulzer, 1994 or Rivner, 1994).
Pitfalls with the use of biomarkers as surrogate
end-points
Biomarkers to be used as surrogate end-points need to be rig-
orously validated, ideally using more than one drug for the
same indication in a particular population (Temple, 1999).
A variety of statistical methods have been proposed to repre-
sent the proportion of treatment effect that is captured by a
surrogate marker (Cowles 2002), and there are many reasons
for dissociation between a surrogate marker and the clinical
end-point it is trying to represent (Prentice, 1989) (Text Box 2).
Although sometimes proposed in place of clinical end-
points, biomarkers are more often measured in addition to
these end-points since this increases the clinicopathological
1696 A. W. Michell et al.
Text Box 2 Reasons for a dissociation between a surrogate
marker and the end-point it is trying to represent
1. False positives
(a) Treatment affects the biomarker but not the disease. A
well-known example occurred in the Cardiac Arrhythmia
Suppression Trial (CAST), where flecainide suppressed
arrhythmias (the biomarker) after myocardial infarction, but
did not reduce mortality (the end-point) (Echt et al., 1991).
(b) Treatment affects a clinically unimportant aspect of patho-
physiology that is faithfully represented by the biomarker.
2. False negatives
Treatment does not alter the biomarker even though it does
alter a useful aspect of the disease pathophysiology. For
example, when testing the therapeutic effect of interferon-g
on recurrent infections in patients with chronic granulomatous
disease, the biomarker (superoxide production by phagocytes)
did not change even though there was clinical benefit (Inter-
national Chronic Granulomatous Disease Study Group, 1991).
3. Insensitive
Treatment does alter the biomarker, but many unexpected
outcomes of the treatment are not represented.
4. More sensitive
In some situations, such as during the long presymptomatic
phase that occurs in Parkinson’s disease, a biomarker sensing
pathological change may be more sensitive than the clinical
outcome.
interpretations that can be made. In this case the marker need
not be specific to one disease. For example, there has been
discussion of the use of C-reactive protein levels as a biomarker
for coronary artery disease since concentrations correlate with
the risk of this disease independently of cholesterol, and are
reduced with treatment (Pearson et al., 2003). As yet a
similar non-specific biomarker has not been found for use in
Parkinson’s disease.
Potential biomarkers for Parkinson’s disease
The large number of potential markers for Parkinson’s disease
will be reviewed by dividing the potential candidates into three
main categories.
1. Imaging as a biomarker
Functional imaging
PET and single-photon emission computed tomography
(SPECT) imaging have numerous potential applications,
including following the decline in neurotransmitter function,
examining metabolic activity (using 18F-fluorodeoxyglucose)
and monitoring regional cerebral blood flow. Furthermore,
new ligands in development may be able to provide patho-
logical information, such as the microglial response to cell
loss (e.g. 11C-PK11195; Cicchetti et al., 2002; Gerhard et al.,
2003) or accumulation of proteins such as a-synuclein and
b-amyloid (Zhuang et al., 2001). In general, whilst PET
scans have greater spatial resolution (especially in 3D
mode), SPECT scans are cheaper and are more widely
available—an important point if such a marker is to be
adopted clinically.
To determine what information is obtained by PET or
SPECT imaging is complicated and comes down to validation
of a particular ligand in a particular situation. For example, 18F-
dopa is taken up by dopaminergic neurons and converted to
18
F-dopamine; therefore a scan using this ligand will provide a
representation of L-dopa uptake through the blood–brain bar-
rier, aromatic amino acid decarboxylase activity that converts
L-dopa to dopamine, and the dopamine storage capacity in
synaptic vesicles. Early pathological validation studies have
shown that striatal 18F-dopa uptake correlates well with nigral
cell count in humans with various diseases (Snow et al., 1993),
and that the striatal 18F-dopa influx constant (Ki) correlates
with dopamine levels, synthetic enzyme activity and nigral cell
counts in monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (Pate et al., 1993).
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It is worth reiterating, however, that this validation is spe-
cific for a particular set of conditions, and that this relationship
may be lost. For example, in early Parkinson’s disease the
uptake of 11C-methylphenidate, a marker of the dopamine
transporter (DAT), is reduced relatively more than 18F-dopa
(Lee et al., 2000), which may represent compensatory down-
regulation of DAT to try to maintain dopamine levels in the
synapse. Furthermore, dopaminergic medications may directly
affect these scans (for example, by possibly causing DAT
downregulation), which would drastically affect their interpre-
tation, especially in the context of neuroprotection (reviewed
recently by Brooks et al., 2003).
Presymptomatic detection. One of the goals of functional ima-
ging is the presymptomatic detection of patients and there are
now several publications to suggest this may be possible. For
example, patients with hemi-Parkinson’s disease showed
reduced uptake on the ipsilateral as well as the expected con-
tralateral side (Schwarz et al., 2000), twin studies have shown a
dopaminergic deficit in asymptomatic twins of patients with
Parkinson’s disease (Burn et al., 1992; Holthoff et al., 1994;
Laihinen et al., 2000), and dopaminergic dysfunction has been
shown in four people after taking 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine prior to the onset of symptoms (Calne et al.,
1985). However, one unresolved issue with these studies is
whether subjects with preclinical imaging abnormalities actu-
ally go on to develop Parkinson’s disease, although data from
one of the twin studies suggests that at least some do (Piccini
et al., 1999b).
At present, PET and SPECT images show significant vari-
ation between normal subjects, such that a preclinical cell loss
of less than 50% will be difficult to detect. There are therefore
ongoing efforts to increase the specificity of the test, including
detailing the topography of the dopaminergic deficiency that
seems to affect the dorsal putamen early in the disease (Sawle
et al., 1994; Morrish et al., 1996b). Alternatively, the positive
predictive value of the test might be improved by scanning only
those at particularly high risk of developing Parkinson’s
disease, such as family members (Piccini et al., 1997) or

those with a parkin mutation (Hilker et al., 2002), but at present
it is not clear who to screen outside these rare familial forms.
Differentiating symptomatic Parkinson’s disease from atypical
Parkinsonian disorders. A different potential diagnostic use for
functional imaging is to help determine which symptomatic
patients really have Parkinson’s disease. Assessment of dopa-
minergic function of the caudate and putamen using 18F-dopa
PET showed that in 64% of patients the PET diagnosis agreed
with clinical diagnosis of Parkinson’s disease, increasing to
70% for progressive supranuclear palsy, but the agreement was
far less for MSA (Burn et al., 1994). 11C-raclopride PET is
emerging as a potential alternative, providing an indirect esti-
mate of synaptic dopamine levels from changes in tracer D2
receptor binding potentials (Brooks et al., 1992; Antonini et al.,
1997). Rather than studying dopaminergic function, some
groups have chosen quantitative 18-fluorodeoxyglucose
PET (18FDG PET) to monitor metabolic activity, and the
results suggest that some patients with clinically diagnosed
striatonigral degeneration can be differentiated from those
with Parkinson’s disease and normal controls because of their
reduced caudate and putamen signal (Eidelberg et al., 1993).
However, one of the problems in interpreting these studies is
that they are not particularly representative of real life, where
the challenge is to distinguish the different forms of parkinson-
ism when the diagnosis is in doubt. In most comparative ima-
ging studies the patients are readily distinguishable clinically.
Furthermore, this clinical diagnosis becomes the gold standard
against which the scan result is compared even though we know
that our clinical diagnosis is not totally accurate [although a
recent study has suggested a positive predictive value of up to
98.6% for the clinical diagnosis of idiopathic Parkinson’s dis-
ease in a specialist movement disorder centre using patholo-
gical confirmation (Hughes et al., 2002)].
Nevertheless, with improved scan resolution and the use of
newer ligands there are likely to be significant advances in the
next few years to enable further clinical use of these promising
tools. Thus it may prove useful, for example, to assess striatal
D2 dopamine receptors on medium spiny GABAergic neurons
using (123I)-S(–)IBZM (iodobenzamide) since in Parkinson’s
disease there is no change in D2 binding, whereas in MSA and
progressive supranuclear palsy it seems to be diffusely reduced
(discussed by Brucke et al., 2000). Alternatively, it may be that
different scanning approaches are adopted, such as the use of
1
H magnetic resonance spectroscopy to study cerebral meta-
bolites (O’Neill et al., 2002) or accurate structural MRI
(Savoiardo, 2003; Yekhlef et al., 2003). As with functional
imaging of the dopaminergic system, the intersubject variation
between normal people and those with Parkinson’s disease
currently limits the accuracy of these tools.
Monitoring disease progression. In the REAL PET study the
18
F-dopa influx constant (Ki) in the putamen was measured in
patients randomized to receive either levodopa or ropinirole
over 2 years. At baseline 11% of patients with the clinical
diagnosis of Parkinson’s disease were felt to have normal
images from the caudate and putamen. In the remainder
Biomarkers and Parkinson’s disease 1697
there was a significant difference in the deterioration of puta-
men 18F-dopa uptake with ropinirole compared with levodopa
(–13% versus 20%, P ¼ 0.02). The investigators concluded
that ropinirole caused
30% slowing of the progression of
Parkinson’s disease over this period (Whone et al., 2003).
The intrasubject test–retest reproducibility of 18F-dopa PET
is relatively good and by using the latest PET machine,
co-aligning three dimensional image sets and looking at
putamen 18F-dopa influx constants (Ki) the variability can
be as low as 2% (Brooks, 2003), suggesting that it is potentially
a powerful way of following disease progression in a patient. In
fact it was estimated that by using 18F-dopa PET it is possible to
detect a 30% protective effect with 80% power in a 2 year study
with 60 patients treated with levodopa versus 60 with a
neuroprotective agent (Brooks, 2003). However, as discussed
above, it is possible that levodopa alters the uptake of 18F-dopa
and therefore changes the 18F-dopa influx constant, which
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would clearly alter the interpretation of the REAL PET results
(Fahn, 2002).
In contrast, in the CALM-PD study, 2b-carboxymethoxy-
3b(4-iodophenyl)tropane (123I-b-CIT) SPECT was used to
study the integrity of the dopaminergic system (reuptake of
dopamine into axons via the DAT) in patients treated with
pramipexole versus levodopa. Overall the results suggested
an
40% reduction in the rate of loss of striatal 123I-b-CIT
uptake with pramipexole compared with levodopa (Parkinson
Study Group, 2000, 2002), with some correlation to clinical
phenotype in that the percentage reduction in striatal 123I-b-
CIT uptake correlated with the change from baseline in the
UPDRS at 46 months (r ¼ 0.4, P ¼ 0.001).
The issues encountered in monitoring disease progression
with 18F-dopa PET, 123I-b-CIT SPECT and (þ)-11C-dihydro-
tetrabenazine PET [which reflects storage of dopamine in
synaptic vesicles via VMAT2 (the vesicular monoamine trans-
porter)] have recently been reviewed elsewhere (Brooks et al.,
2003; Morrish, 2003). As well as use in neuroprotective stu-
dies, these imaging tools have been used to show that cell
transplantation can restore dopaminergic function in line
with clinical improvement (Piccini et al., 1999a), providing
evidence that clinical benefit relates to the dopaminergic activ-
ity within the graft.
Can functional imaging assess the validity of other
biomarkers? Finally, great caution needs to be exercised
when functional imaging is used as a surrogate marker with
which to assess the efficacy of other potential biomarkers. For
example, Wolters and colleagues performed a study comparing
sense of smell with 123I-b-CIT SPECT in first-degree relatives
of patients with Parkinson’s disease (Wolters et al., 2000),
since they are known to have an increased risk of developing
the disease (Payami et al., 1994; Marder et al., 1996).They
hypothesized that the 50 best and worst smellers of a group
of 500 would have significantly different striatal binding of
123
I-b-CIT. However, even if subjects demonstrating a poor
result on a potential new test also have poor SPECT scans it
must be shown that this same group does in fact go on to
1698 A. W. Michell et al.
develop Parkinson’s disease in order to show they could be
good biomarkers.
Transcranial ultrasound
Using a temporal bone acoustic window, it is possible to use
ultrasound to determine the echogenicity of the substantia
nigra (Becker and Berg, 2001). In Parkinson’s disease this tends
to be increased bilaterally, whereas in non-extrapyramidal
neurological disorders it is often normal, although in
30%
of cases this examination could not distinguish these two
groups (Berg et al., 2001b; Walter et al., 2002). As yet the
pathophysiological significance of this increase is not clear, but
it seems to relate to iron and ferritin levels, and potentially
therefore an increase in iron-derived free radicals causing cell
damage (Berg et al., 2002).
There is some evidence to suggest that this technique might
detect presymptomatic disease. For example, the substantia
nigra hyperechogenicity seen in healthy asymptomatic subjects
correlated with a reduction in 18F-dopa uptake in the putamen
using PET (Berg et al., 2002), and psychiatric patients with high
echogenicity developed worse extrapyramidal signs and symp-
toms on neuroleptics compared with those with lower echogeni-
city (Berg et al., 1999, 2001a). Furthermore, elderly people
without a diagnosis of Parkinson’s disease but with substantia
nigrahyperechogenicityshowedmorefrequentandmoresevere
slowing and hypokinesia than age-matched subjects with nor-
mal echogenicity, although it is unknown how many of these go
on to develop frank Parkinsonism (Berg et al., 2001c).
Cardiac metaiodobenzylguanidine (MIBG)
scintigraphy
Many patients with Parkinson’s disease complain of auto-
nomic dysfunction, such as bladder irritability, sweating or
constipation, prior to developing characteristic extrapyramidal
signs. Furthermore, there is post-mortem evidence of Lewy
body formation diffusely within the autonomic nervous sys-
tem, including enteric nerves and cardiac plexus (Qualman
et al., 1984; Singaram et al., 1995; Wakabayashi and Takaha-
shi, 1997). In the light of these findings some researchers have
chosen to study autonomic function as a potential biomarker in
Parkinson’s disease.
MIBG is an analogue of noradrenaline that is transported
into sympathetic neurons and can act as a tracer of catechola-
minergic neurons if labelled with radiolabelled iodine and
detected by scintigraphy. A recent review of the use of such
imaging in a total of 246 Parkinson’s disease patients and 45
cases of MSA suggested that the cardiac to mediastinal uptake
ratio of MIBG could correctly identify idiopathic Parkinson’s
disease with 89.7% sensitivity and 94.6% specificity from the
group with MSA (Braune, 2001).
However, caution must be exercised in interpreting these
promising results since this biomarker is affected in other dis-
eases that might imitate Parkinson’s disease, such as dementia
with Lewy bodies (Yoshita et al., 2001). In addition, we do not
know exactly what the reduced MIBG uptake in the heart of
patients with Parkinson’s disease means since it does not reflect
denervation, and it seems to be reduced even without overt
autonomic failure.
2. Clinical testing procedures
Firstly let us consider diagnosis. Any form of clinical testing
from neuropsychology to clinical neurophysiology relies on
the phenotypic expression of the disease process, and could
therefore not detect the preclinical period of neuronal loss (this
would require a marker reflecting pathology). However, these
testing procedures might be able to sensitively detect subtle
early symptoms and signs in at-risk groups that would
otherwise be missed on routine clinical assessment. They
may therefore effectively shorten the prediagnostic period
and might be useful in precipitating early treatment. For exam-
ple, in Huntington’s disease there is evidence that poor
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performance on tests of attentional set shifting and semantic
verbal fluency can be found in ‘asymptomatic’ gene-positive
individuals (Lawrence et al., 1998), at the time of reduced
striatal D1 and D2 receptor binding on 11C-raclopride PET
(Andrews et al., 1999).
Secondly, a biomarker that accurately measures clinical
phenotype will be of limited use for assessing pathological
progression since it would be affected by purely symptomatic
effects of disease modifying medication (see above in
‘Monitoring disease progression’ – the dopamine agonist
trials). However, clinical markers are essential for monitoring
symptom fluctuation in response to treatment, which is the
ultimate end-point for patients and clinicians. Furthermore,
given that Parkinson’s disease is extremely heterogeneous
(Foltynie et al., 2002a), these markers are likely to help stratify
the diseased population by patterns of presentation and pro-
gression. This might prove helpful in targeting novel treat-
ments, such as cell transplantation, since early data suggest
that some subgroups of the Parkinson’s disease population res-
pond better than others (Freed et al., 2001; Olanow et al., 2003).
Affective and psychological tests
Prior to developing Parkinson’s disease many patients suffer a
range of rather non-specific symptoms, such as depression,
anxiety and musculoskeletal pain, that might herald subse-
quent disease development (Gonera et al., 1997). It is possible
to use depression rating scales and other tools to monitor some
of these symptoms (Montgomery et al., 2000a, b), but the
results tend to be rather variable, which is partly because
the early symptoms of Parkinson’s disease might be similar
to prodromal depressive symptoms and because rating scales
such as the Beck Depression Inventory (Beck et al., 1961) are
not specifically designed to capture the relevant early depres-
sive symptoms.
An alternative might be to develop a test that concentrates on
certain features of the depression that are more specific to
Parkinson’s disease patients, such as feelings of self-reproach
(Huber et al., 1990) or anxiety-related depression (Hoogendijk

et al., 1998). Early studies suggested that Parkinson’s disease
sufferers showed emotional repression, self-reliance, introver-
sion and punctuality, although this was based on small numbers
of patients and anecdotal evidence (for reviews see Todes and
Lees, 1985; Menza, 2000). Nevertheless, it may be that a per-
sonality questionnaire looking at such traits may go some way
to predicting mood disorder and help with early diagnosis in
susceptible individuals, although the issue of identifying the
latter group remains.
There is evidence that cognitive dysfunction may affect
executive processes and precede the motor manifestations of
Parkinson’s disease both in humans and a slowly progressing
animal model of Parkinson’s disease (Schneider and Pope-
Coleman, 1995; Brown et al., 1998). This may remain unre-
cognized by relatives because external cues in the environment
and a familiarity with daily tasks allow the sufferer to function
normally. It is possible, however, that complex neuropsycho-
logical tests requiring an intact working memory and executive
function may pick up these deficits early in susceptible people
(Cooper et al., 1991). However, one study using the Tower of
London test of problem-solving and executive function did not
reliably detect early Parkinson’s disease (Owen et al., 1992).
Beyond a role in diagnosis it seems increasingly likely that
cognitive behaviour may provide a powerful way of defining
disease heterogeneity and increasing our understanding of the
neural correlates of cognitive dysfunction within the disease
(Lewis et al., 2003a, b; Foltynie et al., 2004).
Tests of motor performance
Any test of motor performance in Parkinson’s disease can
really be viewed as an extension of the clinical examination,
which has been refined in the light of post-mortem data to be as
diagnostically accurate as possible (Rajput et al., 1991; Hughes
et al., 1992b). Performance of complex tasks such as writing,
visually guided movement or sequential tasks has been used to
examine actions that involve high-level motor control, whereas
some researchers have focused on simple parameters, such as
the velocity of movement or reaction time.
Using these procedures there is some evidence of a motor
abnormality before symptoms are declared by the patient. So,
for example, when testing patients with unilateral symptoms of
Parkinson’s disease, motor abnormalities have frequently been
detected on the ‘normal’ side (Horstink and Morrish, 1999).
Visuomotor testing has also revealed impairments on the
asymptomatic side of hemiparkinsonian patients in the control
of movement direction during tracing tests, and of movement
velocity during target tracking (Hocherman and Giladi et al.,
1999). However, many tests looking at simple movements are
unrewarding in their conclusions if taken in isolation (Kraus
et al., 2000; Montgomery et al., 2000a, b) and contingent on
mood and motivation.
Overall, with refinement there may be a testing algorithm
that might help in the early diagnosis of disease. To be really
useful it would need to differentiate atypical cases from true
Parkinson’s disease when there is clinical uncertainty, and at
Biomarkers and Parkinson’s disease 1699
present there are no trial data to support this. Therefore at the
present time these tests would seem to be more useful in
monitoring clinical progression and response to symptomatic
treatment rather than diagnosis.
Clinical neurophysiology
There are two rather different clinical neurophysiological
approaches to Parkinson’s disease. The first of these has
been to describe and subdivide the exact motor phenotypes
resulting from disease of the basal ganglia as there are neuro-
physiological counterparts of the key clinical features of the
disease. Thus, tremor can be monitored by surface EMG or
accelerometer, bradykinesia by reaction times or ballistic
movements, and rigidity by surface EMG or long-latency
stretch reflexes (Valls-Sole and Valldeoriola, 2002). This
descriptive approach allows the objective monitoring of the
effects of treatment and any change in clinical signs over time.
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Furthermore, it provides valuable insight into the pathological
cause of these clinical complaints, which should help us under-
stand and subclassify this heterogeneous disease.
Alternatively, we know that pathological changes occur in
Parkinson’s disease outside the basal ganglia, which, if they
can be detected and accurately monitored, might themselves
provide a useful marker. For example, it seems likely that
sensory motor integration is affected in Parkinson’s disease,
and could be measured using somatosensory evoked potentials
(Rossini et al., 1989), or transcranial magnetic stimulation to
reveal abnormal higher cortical processing (Lewis and
Byblow, 2002). Furthermore, there is some evidence for a
reduced amplitude and slope of the cerebral electrical activity
that precedes and accompanies voluntary internally paced
movements (the Bereitschaftspotential) in Parkinson’s disease
compared with controls (Filipovic et al., 2001). The sympa-
thetic skin response and electrocardiogram R–R interval vari-
ation have been used to help confirm and monitor clinical
dysautonomia (Zakrzewska-Pniewska and Jamrozik, 2003),
which may help more in stratifying disease than in diagnosis
or monitoring disease progression. Finally, several groups
have investigated the use of anal sphincter EMG, which can
help distinguish subjects with MSA from normals, but unfor-
tunately it is unable to reliably distinguish MSA from Parkin-
son’s disease, given the range of neurogenic changes in
Parkinson’s disease, especially in advanced disease (Giladi
et al., 2000; Libelius and Johansson, 2000; Vodusek, 2001).
Olfaction
The loss of smell detection, identification or discrimination
often goes unnoticed early in neurodegenerative disease,
before the development of extrapyramidal signs. In
Parkinson’s disease this may in part reflect neurodegeneration
within the olfactory bulb since there is evidence that this might
precede both nigral degeneration and symptoms (Braak et al.,
2002). Support for the presymptomatic deterioration of
olfaction has been provided by Berendese and colleagues,
who showed olfactory dysfunction in first-degree relatives
of patients with Parkinson’s disease together with reduced
1700 A. W. Michell et al.
striatal dopamine transporter binding, as assessed by 123I-b-
CIT in four out of 25 SPECT scans of these hyposmic relatives
(Berendse et al., 2001). Two of the relatives with hyposmia and
reduced striatal dopamine transporter binding subsequently
developed Parkinson’s disease, suggesting that olfaction
might be a useful presymptomatic biomarker.
Once symptoms have developed, it has been suggested that
olfactory dysfunction might help distinguish patients with
idiopathic Parkinson’s disease from healthy subjects (Tissingh
et al., 2001). Perhaps more usefully, however, it may be that
alteration in the sense of smell can also help distinguish true
cases of Parkinson’s disease from their imitators, such as pro-
gressive supranuclear palsy (Doty et al., 1993; Hawkes, 2003).
In a recent study it was found that patients with idiopathic
Parkinson’s disease were either anosmic or hyposmic, whereas
all but one of the patients with MSA or progressive supranuc-
lear palsy had only mild to moderate hyposmia (Muller et al.,
2002), and patients with corticobasal degeneration or psycho-
genic movement disorders were found to be normosmic.
Vision
There are many ways in which vision might be affected in
Parkinson’s disease (Bodis-Wollner and Onofrj et al., 1987).
For example, it has been suggested that colour vision and con-
trast sensitivity might be abnormal as a result of a change in
intraretinal dopaminergic transmission in amacrine and inter-
plexiform cells, and colour vision has indeed been found to be
abnormal in some Parkinson’s disease patients (Buttner et al.,
1995) but not all (Vesela et al., 2001). Furthermore, there seem
to be differences in contrast sensitivity, visual evoked responses
and electroretinograms in Parkinson’s disease patients com-
pared with controls, but the diseased and normal values overlap
(Price et al., 1992). Given that the pathological process in
Parkinson’s disease affects retinal cells, it may be that tests
of retinal function will correlate more closely with pathological
changes in the basal ganglia than clinical phenotype.
On the other hand, abnormalities of eye movement might
turn out to be more closely related to motor phenotype than
pathology since, for example, it seems that visual landmarks
improveantisaccadeperformance(asaccademadeintheoppos-
ite direction to a stimulus) in Parkinson’s disease more than
controls, in a fashion analogous to target-directed pointing
(Briand et al., 1999). Several studies have recorded eye move-
ments in Parkinson’s disease compared with controls, and
although there does seem to be some difference between
Parkinson’s disease patients and controls during voluntary
saccade paradigms (Briand et al., 1999) their potential as
biomarkers is not fully characterized.
3. Biochemical and genetic tests
The ideal biochemical biomarker would need to be easily
measured and to reflect accurately the ongoing degenerative
process in the basal ganglia. Furthermore, any correlation with
clinical phenotype should only arise secondarily to this
relationship and the marker should not, for example, be influ-
enced by symptomatic drug therapies.
Blood tests
Parkinson’s disease is thought to be due, at least in part, to
increased oxidative stress (Jenner, 2003) and considerable
effort has been spent in the search for a marker of this process.
For example, it has been noted that patients with Parkinson’s
disease show a selective reduction in mitochondrial complex I
in their substantia nigra (Schapira et al., 1990) and that platelets
exhibit a similar deficiency (Parker et al., 1989). Platelets have
been used for a long time to model serotonergic and dopamin-
ergic neuron behaviour (Da Prada et al., 1988), and since they
are easily collected they make appealing candidates as periph-
eral biomarkers of oxidative stress, rather than other sources
such as skeletal muscle (Blin et al., 1994). However, there may
be a degree of tissue specificity, and at least one study has
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reported a lack of difference in complex I levels in the platelets
of patients with Parkinson’s disease versus controls (Mann
et al., 1992), which would limit the ability of peripheral assays
to detect central changes.
The concentrations of several other potential markers of oxid-
ative stress have been measured in blood, such as malondi-
aldehyde, superoxide radicals (Ilic et al., 1999), the coenzyme
Q10 redox ratio (Gotz et al., 2000), 8-hydroxy-20 -deoxy-
guanosine from oxidized DNA and 8-hydroxyguanosine
from RNA oxidation (Kikuchi et al., 2002; Abe et al., 2003).
The levels tend to be abnormal in Parkinson’s disease com-
pared with control groups, providing valuable insight into the
nature of the oxidative stress, but none is sufficiently robust to be
useful as a diagnostic biomarker of the disease process in clinical
practice. A similar situation exists if instead the levels of protec-
tive enzyme systems are compared, such as glutathione reduc-
tase, or copper and zinc superoxide dismutase (Ilic et al., 1999).
An alternative haematogenous biomarker for Parkinson’s
disease may arise from studies looking at dopamine metabo-
lism in the periphery. There is some evidence of a reduction in
dopaminergic transporter immunoreactivity in lymphocytes of
Parkinson’s disease patients (Caronti et al., 2001). In addition
there is evidence that platelet monoamine oxidase B activity is
increased and plasma b-phenylethylamine is reduced in
patients with Parkinson’s disease, and that this may be reversed
by selegiline treatment (Bonuccelli et al., 1990; Zhou et al.,
2001). Attempts to detect a difference in plasma homovanillic
acid in Parkinson’s disease patients versus controls have so far
been unrewarding (Jenner et al., 1993).
Finally, some researchers have opted to look instead at
a-synuclein in platelets of controls versus patients with
Parkinson’s disease since there is evidence for a dose effect
of this protein (Singleton et al., 2003) as well phosphorylation
in human synucleinopathies (Fujiwara et al., 2002). Unfortu-
nately, although a-synuclein is present in platelets (Hashimoto
et al., 1997) early studies do not suggest there is any difference
in the amount in controls versus Parkinson’s disease (Li et al.,
2002) (A.W. Michell, L.M. Luheshi, M.G. Spillantini,
R.A. Barker, unpublished results).

CSF
CSF is a less appealing source of biomarkers in comparison
with blood because of the difficulty of obtaining samples. None
the less, many researchers have investigated its chemical com-
position in Parkinson’s disease, especially in relation to poten-
tial markers of oxidative stress, some of which have also been
investigated in blood. For example, the levels of 8-hydroxy-20 -
deoxyguanosine and 8-hydroxyguanosine were found on aver-
age to be elevated in Parkinson’s disease (Kikuchi et al., 2002;
Abe et al., 2003). Similarly, the levels of the reactive oxygen
species malondialdehyde have been recorded in the CSF and
found to be significantly increased in Parkinson’s disease com-
pared with controls (Ilic et al., 1999).
Numerous other potential CSF biochemical markers have
been studied. These have revealed that in Parkinson’s disease
compared with control subjects there are reduced levels of CSF
b-phenylethylamine that correlated negatively with Hoehn and
Yahr clinical stage (Zhou et al., 1997). Furthermore, ventri-
cular CSF levels of orexin were lower in Parkinson’s disease
patients than controls, especially in those with advanced dis-
ease (Drouot et al., 2003). On the other hand, there seem to be
similar amounts of a-synuclein (Borghi et al., 2000) and insu-
lin (Jimenez-Jimenez et al., 2000), and only slightly differing
levels of homovanillic acid, 5-hydroxy-indoleacetic acid and
acetylcholinesterase (Hartikainen et al., 1992; Jenner, 1993;
Loeffler et al., 1995).
Of course the above studies throw some light on disease
pathogenesis and were not carried out purely to detect potential
biomarkers, and so as diagnostic tests they would provide at
best poor sensitivity and specificity, like the blood tests
described earlier. This may be in part because of treatment
or compensatory mechanisms that maintain the levels of dopa-
mine and its metabolites by increased production from the
surviving cells (LeWitt et al., 1992; Zigmond et al., 2002).
Genetic testing
For the majority of patients there is no clear link between
genotype and the development of Parkinson’s disease,
although genetic susceptibility is suggested by several lines
of evidence, such as the familial clustering of Parkinson’s
disease (Sveinbjornsdottir et al., 2000; Foltynie et al., 2002b)
and the increased incidence of Parkinson’s disease in the
identical twin of some patients, especially the young (Burn
et al., 1992; Tanner et al., 1999). Of course there are extremely
rare and well publicized autosomal dominant cases of
Parkinson’s disease (Polymeropoulos et al., 1997; Kruger
et al., 1998), as well as autosomal recessive transmission
(Kitada et al., 1998). For these cases alone, genetics is uniquely
useful to help diagnosis and to help subdivide this hetero-
geneous disease, since patients with the autosomal dominant
or recessive types of disease tend to have rather different
clinical courses.
In sporadic Parkinson’s disease the use of genetic markers is
not so clear-cut (Foltynie et al., 2002b; Dekker et al., 2003).
There have been a number of candidate gene studies using
Biomarkers and Parkinson’s disease 1701
techniques such as familial linkage analysis, direct DNA
sequencing and allelic association studies in an attempt to
associate specific genes, such as tyrosine hydroxylase and
many others, with Parkinson’s disease (Warner and Schapira,
2003). There has been little success for sporadic disease, but
one hope is that if an association is found it might help stratify a
diseased population; however, it would not be powerful
enough to make predictions for a single patient, given the
number of unknown interacting genetic and environmental
factors, differing gene penetrance and so on.
Future directions
Advances in our understanding of genetics may well eventually
provide useful biomarkers for Parkinson’s disease. For exam-
ple, single-nucleotide polymorphisms and haplotype maps
could be used to investigate subtle genetic differences in
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drug receptors in the light of differing clinical responses to
a new drug. This could help determine the molecular basis for
clinical variation, and once validated the single-nucleotide
polymorphism or haplotype map might serve as a predictive
biomarker of clinical response. Alternatively, RNA profiling
can provide a map of the genes that are actively being tran-
scribed that, once correlated to drug efficacy, could help
explain the biochemical basis of that efficacy. In patients it
may eventually be possible to use this technique on leucocytes
in a blood sample to gain insight into why a patient is respond-
ing well or adversely to a new drug. Given the complex inter-
action between genes and their environment, these techniques
are unlikely to help with diagnosis or individual risk prediction
in Parkinson’s disease.
An alternative systems biology approach is to look further
down the line and assess the pattern of peptide fragments (pro-
teomics) or metabolites (metabonomics) from a peripheral
tissue sample. Using techniques such as nuclear magnetic reso-
nance spectroscopy, we can test for a large variety of com-
pounds in different tissues and subsequently compare the
patterns achieved (which represent a metabolic profile) in
the diseased and control state to provide an insight into the
metabolic defect in disease. Recently, such a technique has
been shown to be powerful enough to help diagnose coronary
heart disease (Brindle et al., 2002). For Parkinson’s disease this
technique might help presymptomatic diagnosis, as well as
improve our understanding of the metabolic defect in disease,
drug toxicology and the reason that some patients respond
better to treatment than others.
Conclusions
There is clearly a need for biomarkers that accurately reflect
pathological change, given the advent of putative neuropro-
tective agents. There is already evidence that this is possible to
some extent using PET or SPECT imaging of the basal ganglia,
but an appealing alternative would be to gain insight into the
pathological changes from a continuously variable biochem-
ical marker that can be assayed economically and easily.
1702 A. W. Michell et al.
Text Box 3 Characteristics of the ideal biomarker that is
designed to reflect a change in pathological or clinical trait X
Close (first-degree) association with X without relying on inter-
mediate variables, thereby minimizing the risk of dissociation.
It must sensitively reflect even small changes in X.
Treatment has no direct effect on the biomarker; it only changes
with a true change in X.
The biomarker changes linearly (either negatively or positively)
in response to a change in X.
Measurements are reproducible at a different time or in a
different centre.
The biomarker should ideally capture all changes in X so that
no information is lost.
The optimal clinical biomarker should be cheap, non-invasive
and quick to measure by untrained staff.
Appropriately thorough validation of the above (depends on
the use of the biomarker and implications of error).
Alternatively, a new motor, neurophysiological or neuro-
psychological biomarker may provide some form of objec-
tive measure of clinical phenotype. As well as potentially
providing another objective end-point for treatment, this type
of clinical biomarker will help stratify this heterogeneous
disease.
The inaccuracy of our clinical diagnosis of idiopathic
Parkinson’s disease is well recognized, and hence there is a
demand for a diagnostic biomarker. Markers reflecting patho-
logy may allow the earliest presymptomatic diagnosis,
whereas either clinical or pathological markers may allow
the differentiation of true idiopathic Parkinson’s disease
from its many imitators once symptoms are overt.
Overall, it is clear that no biomarker will be able to do it
all in Parkinson’s disease (Text Box 3). Given the hetero-
geneity of disease, it is likely that a biomarker will only
prove useful in certain situations, whilst the strength of
the clinical examination is its breadth and ability to detect
non-dopaminergic symptoms. In the search for improved
diagnostic fidelity it may be that a stepwise approach is
required despite the potential pitfalls in combining diagnostic
tests. For example, clinical assessment might be supplemen-
ted by a specific neuropsychological questionnaire or phy-
siological test, with subsequent confirmation by imaging or a
biochemical marker. Finally, any biomarker used in clinical
trials as a surrogate end-point requires extensive evaluation
over years in different populations of Parkinson’s disease
patients to ensure its validity. The key in each situation is
to appreciate the limitations of the biomarker and what it
actually measures.
Acknowledgements
The authors’ work has been supported by grants from the
Wellcome foundation, MRC and Parkinson’s Disease Society.
AWM holds a PDS studentship and Raymond and Beverly
Sackler studentship.
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