CHAPTER SEVEN

Biomarkers of Parkinson’s Disease:

An Introduction
Nataliya Titova*,1, Mubasher A. Qamar†,‡,§, K. Ray Chaudhuri†,‡,§
*Federal State Budgetary Educational Institution of Higher Education “N.I. Pirogov Russian National
Research Medical University” of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
†
National Parkinson Foundation International Centre of Excellence, Kings College and Kings College
Hospital, London, United Kingdom
‡
Maurice Wohl Clinical Neuroscience Institute, Kings College, London, United Kingdom
§
National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre (BRC) and
Dementia Unit at South London and Maudsley NHS Foundation Trust, London, United Kingdom
1
Corresponding author: e-mail address: nattitova@yandex.ru

Contents
1. Introduction 184
2. The Types of Biomarkers 184
3. Neuroimaging 192
4. Neuroinflammation 192
5. The Future 193
Acknowledgments 193
References 193

Abstract
The development of biomarkers is of great importance in Parkinson’s disease (PD) as it
may contribute to confirmation and support of the diagnosis, tracking of progression,
and prediction of the natural history of PD. Biomarkers also help in the identification of
targets for treatment and measuring the efficacy of interventions. Biomarkers are, there-
fore, crucial to understanding the pathophysiology of PD, the second commonest neu-
rodegenerative disorder in the world. Modern understanding of PD suggests that it is a
multipeptide, multiorgan disorder presenting with a heterogeneous clinical condition,
both motor and nonmotor. Biomarkers need to reflect this neuropathological and clin-
ical heterogeneity of PD. In this review, we outline some key advances in the field of
clinical, genetic, neuroimaging, and tissue-based biomarkers proposed or used for
PD. The individual sections will be covered in relevant chapters and our review is largely
a primer aimed to alert readers to the current state of the various biomarkers proposed
for PD. In doing so, we have also underlined the important role multimodal rather than
single biomarkers could play in our future understanding of PD.

International Review of Neurobiology, Volume 132 # 2017 Elsevier Inc. 183

ISSN 0074-7742 All rights reserved.
http://dx.doi.org/10.1016/bs.irn.2017.03.003
184 Nataliya Titova et al.

1. INTRODUCTION
A biomarker is defined as a tool or a collection of tools that can objec-
tively measure multitude of events which provides information on the nor-
mal, pathological, or pharmacological processes taking place during the
course of a disorder. The Biomarkers Definitions Working Group have
met and attempted to define biomarkers as “a characteristic that is objec-
tively measured and evaluated as an indicator of normal biological processes,
pathogenic processes or pharmacological responses to a therapeutic
intervention” (Biomarkers Definitions Working Group, 2001). Biomarkers
are needed for Parkinson’s disease (PD) to address several issues (Table 1),
some of which remain key unmet needs and a challenge for research.

2. THE TYPES OF BIOMARKERS

Several forms of biomarkers have been described and validated. These
include clinical symptoms (comprising of motor and nonmotor symptoms
Table 1 The Need and Potential Utility for Biomarkers in Parkinson’s Research

To confirm and support diagnosis

Motor diagnosis
Possibly prodromal diagnosis
To track progression of disease
Motor progression
Nonmotor progression
Holistic progression
To predict trajectory of disease
Early vs advanced/complex PD vs palliative stages of PD (Fig. 1)
To identify targets for treatment
Motor subtypes
Nonmotor subtypes
Individualized precision medicine
To address the efficacy of interventions
Outcome measures (clinical, imaging, biochemical)
Parkinson’s and Biomarkers 185

(NMS) and/or relevant validated scales that chart progression of PD), genet-
ics, neuroimaging (central and peripheral nervous system), and biochemical
(tissue-derived) assessments. These are listed in Table 2.
Biomarkers could also be classified as per Sharma et al. (2013) who pro-
posed the following groupings:
• In vivo (neuroimaging, neurophysiology (muscle action potential),
polysomnography)
• In vitro (biochemical/genetics from tissue samples)
• Pathological (α-synuclein, dopamine transporter loss, iron accumulation)
• Neurobehavioral (depression, fatigue, cognition)
• Clinical (Table 2)
The role of biomarkers has become crucial to better define and understand
PD which is no longer considered a motor disease alone. PD is now regarded
as a syndrome characterized by a preprodromal stage progressing to the
motor syndrome of PD followed by a palliative stage (Antonini et al.,
2015; Jellinger, 2015; Titova, Padmakumar, Lewis, & Chaudhuri, 2016)
(Fig. 1). Pathophysiology of PD includes multiple neurotransmitter dysfunc-
tion, dopaminergic and nondopaminergic deficits, and a complex medley of
molecular mechanisms causing widespread (central and peripheral nervous
system) neuronal degeneration with Lewy body deposition (Braak et al.,
2003; Halliday, Holton, Revesz, & Dickson, 2011; Halliday, Lees, &
Stern, 2011; Titova et al., 2016). It is now widely appreciated that, owing
to the heterogeneity of PD, single biomarkers may not be useful and a mul-
timodal approach with motor and NMS-driven biomarkers is required
(Chaudhuri, 2016). For instance, availability of robust biomarkers for the
different stages of PD as shown in Fig. 1 would allow development of pre-
cision and “stage-specific” therapies. Such an approach is likely to support
basic scientists as well as translational research and clinicians to effectively
diagnose, follow, and understand the motor and nonmotor syndrome of
PD, currently an unmet need.
The syndromic nature of PD is further exemplified by four dominant
neurotransmitter dysfunctions of varying severity (Fig. 2) which underpins
the condition and is likely to express clinically as nonmotor subtypes of PD
(Sauerbier, Jenner, Todorova, & Chaudhuri, 2016). Valid biomarkers for
PD, therefore, need to reflect the heterogeneity of underlying pathophysi-
ology. Recent evidence from a 2-year follow-up study of de novo PD sug-
gests that single and cognitive biomarkers may not be adequate. Thirty
possible biomarkers were examined in this study and the authors conclude
that a multimodal approach, with clinical, biochemical, and laboratory-
based biomarkers, is needed (Mollenhauer et al., 2016).
Table 2 A List of Proposed and Possibly Relevant Clinical, Biochemical, and Genetic Biomarkers
Type of Biomarker Effect Key References
Clinical
Prodromal NMS Schrag, Horsfall, Walters, Noyce, and Petersen (2015)
RBD Progression to α-synucleinopathy Postuma, Gagnon, and Montplaisir (2013)
REM sleep behavior PSG evidence of RBD Sixel-D€
oring, Trautmann, Mollenhauer, and
events Trenkwalder (2014)
Late-onset hyposmia/ Progression to PD Jennings, Siderowf, Stern, and Marek (2013)
anosmia
Episodic major Prodromal PD feature Jennings et al. (2013) and Sauerbier and Chaudhuri
depression (2015)
Constipation Higher risk of developing PD
Excessive daytime Higher risk of developing PD
somnolence
Fatigue Higher risk of developing PD Kang, Ma, Lim, Hwang, and Kim (2013)
Abnormal color Higher risk of developing PD Diederich et al. (2010)
vision/visual perception
Erectile dysfunction Higher risk of developing PD Gao et al. (2007)
Pain (often unilateral) Pain often evident on side first affected at motor PD Lin, Wu, Chang, Chiang, and Lin (2013)
diagnosis
Cognitive impairment Recent evidence from PPMI cohort Chahine et al. (2016)
 Motor symptoms
Tremor Could be prodromal Schrag et al. (2015)
Postural instability Prodromal and advancing motor PD Delenclos, Jones, McLean, and Uitti (2016) and Schrag
et al. (2015)
Dyskinesias Advancing motor PD
Micrographia May be evident in prodromal stage
Scales
UPDRS Well established for motor progression
Scopa Autonomic Evidence from DeNoPa study Mollenhauer et al. (2016)
PD NMS scale Evidence from DeNoPa study
Genetics (proposed)
GBA 5%–10% PD Beavan et al. (2015)
LRRK2 (G2019S Accounts for 2%–3% of all PD Klein and Schlossmacher (2007) and Houlden and
mutation) Singleton (2012)
α-syn (SNCA), Parkin, Weak evidence
PINK1, DJ-1
Biochemical
Blood based Chahine, Stern, and Chen-Plotkin (2014)
α-Synuclein Unclear and depends on oligomeric vs total and Chahine et al. (2014)
phosphorylated
Both " and #reported
Continued
Table 2 A List of Proposed and Possibly Relevant Clinical, Biochemical, and Genetic Biomarkers—cont’d
Type of Biomarker Effect Key References
DJ-1 Studies suggest not useful for diagnosis even after Chahine et al. (2014) and Shi, Zabetian, et al. (2010)
quality control
Uric acid and serum CEP 1347 trial (PRECEPT) cohort-based data show Cipriani, Chen, and Schwarzschild (2010)
urate hazard ratio for receiving dopaminergic therapy
declined with " serum urate. Correlation with striatal
beta CIT uptake
EGF # Values linked to cognitive performance Chahine et al. (2014) and Pellecchia et al. (2013)
Apo A1 Proposed unbiased biomarker " may reduce risk of Chahine et al. (2014), Gao, Simon, Schwarzschild, and
developing PD and predictor of UPDRS III score Ascherio (2012), and Lee et al. (2013)
Links with statins that " Apo A1
Cerebrospinal fluid Kroksveen, Opsahl, Aye, Ulvik, and Berven (2011)
based
α-Synuclein Variations between total # and oligomeric " and Sharma et al. (2013)
phosphorylated "
DJ-1 #
GBA activity #
Aß-42 # Levels of t-tau, p-tau Savica, Grossardt, Bower, Ahlskog, and Rocca (2013)
Link with NMS including cognitive
Neurofilaments Maybe useful in differential diagnosis between PD
and MSA
α-Synuclein A real-time quaking-induced conversion Fairfoul et al. (2016)
RT-QuIC RT-QuIC-based assay which can detect α-synuclein
aggregation in cerebrospinal fluid
Other tissues
Submandibular gland Peripheral evidence of α-synuclein deposition Adler et al. (2016)
Skin biopsy Cutaneous α-synuclein deposition Gibbons, Garcia, Wang, Shih, and Freeman (2016)
Colonic biopsy Phosphorylated α-synuclein deposition across the Shannon et al. (2012)
myenteric plexus, submucosal layer, as well as the
mucosal nerve fibers of the intestine
Urine 8-Hydroxydeoxyguanosine, a measure of oxidative Sato, Mizuno, and Hattori (2005)
stress
Phosphorylated LRRK2 predicts phenotype with Shi, Huber, and Zhang (2010)
cognitive impairment
Saliva Genetic testing (GBA, LRRK2) Klein and Schlossmacher (2007) and Houlden and
Singleton (2012)
Feces (fecal microbiota) Significant differences and # of “protective” gut Scheperjans (2016)
microbiota composition in PD vs controls.
However, consistency needs further confirmation
None are robust in isolation. Multimodal validity is being tested. Neuroimaging is discussed elsewhere.
α-syn (SNCA), α-synuclein; Aβ-42, A beta containing amyloid; AMSA, multiple system atrophy; Apo A1, apolipoprotein A1; CIT, 2β-carbomethoxy-3β-(4-iodophenyl)tropane;
DeNoPa, the de novo Parkinson’s cohort; EGF, epidermal growth factor; GBA, glucocerebrosidase; LRRK2, leucine-rich repeat kinase 2; NMS, nonmotor symptoms; PD,
Parkinson’s disease; PPMI, Parkinson’s progressive markers initiative; PSG, polysomnography; RBD, REM sleep behavior disorder; REM, rapid eye movement; UPDRS, Unified
Parkinson’s Disease Rating Scales.
 Neu
ron
al lo
ss

Good/predictable response to Functional consequences:

dopamine agonist therapy Repeated falls
Increasing dependency
No motor fluctuations Risk of pneumonia

Fluctuations
Delayed “on” Institutionalization
Aging
Wearing “off” Palliative care
Gender, smoking Increasing NMS burden
Balance problems

Preprodromal Prodromal Stable Unstable Advanced Palliative

PD PD PD PD PD PD

Genetics/substantia
nigra ultrasound imaging Nonmotor symptoms:
Motor symptoms:
Mild dementia
>2 h “off” per day
Neuropsychiatric
Hyposmia 1 h with troublesome dyskinesia
Nonmotor fluctuations
REM sleep behavior disorder Levodopa >5 times per day
Nighttime sleep dysfunction
Excessive daytime sleepiness Dysphagia
Nontransient hallucinations
Depression
Anxiety

Molecular mechanisms Neurodegeneration

start affecting DA, Ach, NA, Progression: motor and nonmotor symptoms
5HT, others (in life manifest symptoms)

Fig. 1 The proposed natural history pattern of Parkinson’s disease. It is to be noted that the neuronal loss in PD is unlikely to follow a linear
pattern (as suggested in the figure) and the relevant line is a schematic representation. Ach, acetylcholine; DA, dopamine; NA, noradrenaline;
5HT, serotonin. Adapted from Chaudhuri, K. R., & Fung, V. S. C. (2016). Fast facts: Parkinson’s disease (4th ed.) (p. 9). Oxford: Health Press Limited.
 The Parkinson¢s syndrome

A mixed pattern
Cholinergic Noradrenergic Serotonergic
with a dominant
syndrome syndrome syndrome
DA dysfunction

Classical PD
Central Peripherals Abnormal cardiac
MIBG DAS-B PET imaging
Syndrome (Pavese, Metta, Bose, Chaudhuri, &
Brooks, 2010; Pavese et al., 2012)
MS + NMS
In vivo imaging in Dysautonomia
Intestinal
untreated and
dysfunction
early PD Orthostatic
(Gjerløff et al., 2015) Fatigue
(Shimada et al., 2009)
hypotension
Excessive daytime
Depression/anxiety sleepiness

Clinical tests ? Akinetic rigid Dyskinesias

(Williams-Gray et al., 2009; (Espay, LeWitt, & Kaufmann,
Weintraub et al., 2015) 2014) (Politis et al., 2010)

MCI at
presentation/dementia

Apathy
Dopamine deficiency

Fig. 2 The multineurotransmitter basis of Parkinson’s disease and the need for multimodal biomarkers that reflect the heterogeneity of the
Parkinson’s syndrome. Taken from Titova, N., Padmakumar, C., Lewis, S. J., & Chaudhuri, K. R. (2016). Parkinson’s: A syndrome rather than a dis-
ease? Journal of Neural Transmission (in press).
192 Nataliya Titova et al.

3. NEUROIMAGING
Neuroimaging techniques and modalities can generate high-
resolution data and are now used commonly to support and validate the clin-
ical diagnosis of PD (Pavese & Brooks, 2009). Magnetic resonance imaging
(MRI) and transcranial sonography (TCS) are commonly available and less
expensive which can noninvasively track pathways of molecular targets that
are of relevance to the parkinsonian neurodegenerative process. Examples
will include the use of MRI with T2-weighted fluid-attenuated inversion
recovery sequences which can detect nigral or basal forebrain degeneration
in PD. Using diffusion tensor imaging, MRI can also show subcortical white
matter degeneration. Voxel-based morphometry is also a useful MRI tech-
nique. TCS can show increased nigral iron deposition in susceptible healthy
older individuals (Mahlknecht, Seppi, & Poewe, 2015). Single-photon
emission tomography and positron emission tomography (PET) are more
expensive and are usually used with cyclotron-generated radioactive meta-
bolic tracers to assess function at a receptor level and can also be used as sur-
rogate marker for diagnosis, monitoring disease severity as well as
progression. Imaging the dopaminergic system is the key approach in PD,
although imaging other neurotransmitter systems is becoming increasingly
relevant (Fig. 2). Furthermore, dopamine-based neuroimaging strategies
can also be selectively combined with a range of clinical scales, symptoms,
and biochemical markers to increase the diagnostic certainty of PD.

4. NEUROINFLAMMATION
In PD, postmortem studies as well as specific imaging using PET and
tissue sampling suggest that neuroinflammation and microglial activation are
common and could even occur in the prodromal stage (Hirsch & Hunot,
2009; Moehle & West, 2015). Tissue-based cytokines have been proposed
as biomarkers and indeed have been linked to depression, anxiety, as well as
cognitive dysfunction (Bufalino, Hepgul, Aguglia, & Pariante, 2013).
A detailed discussion of all proposed biomarkers is beyond the scope of
this chapter and will be covered in relevant cognition, neuroimaging, and
nonmotor chapters. For detailed discussion, we would like to refer the
readers to a few excellent current reviews cited in Biomarkers Definitions
Working Group (2001), Sharma et al. (2013), Chahine et al. (2014), and
Miller and O’Callaghan (2015). A number of prospective cohort studies
Parkinson’s and Biomarkers 193

have now been initiated to address the role of clinical, genetic, and other
biomarkers and their value in clinical practice. These include the PD bio-
marker program, the Parkinson’s progression markers initiative, the Kassel
DeNoPa cohort study, and the Parkinson’s NMS longitudinal study
(NILS) among others and are likely to report on the value of multimodal
biomarker approach to PD in future.

5. THE FUTURE
As this review suggests, a single biomarker is unlikely to be successful
for PD. In the last decade, new techniques such as proteomics, met-
abolomics, as well as transcriptomics have emerged. These tools can perform
mass analyses and identify small changes in protein function, track metabo-
lites, and identify RNA profiles in a variety of tissues and fluids from healthy
and affected people. Genetic and clinical biomarkers continue to evolve par-
ticularly with the emergence of the concept of discrete motor and nonmotor
subtypes of PD (Sauerbier et al., 2016). Functional imaging targeting
nondopaminergic pathways in the brain and periphery will add to the range
of biomarkers available for future. In addition, in clinical practice milestones
of PD need to be better signposted by biomarkers. For instance, in future,
the concept of “advanced” PD may be designated by a range of clinical,
biochemical, and imaging biomarkers. Such studies are currently under
way. The value of a multimodal biomarker approach has been illustrated
in the study by Mollenhauer et al. (2016) and is likely to become the method
of choice for tracking and managing a complex heterogeneous condition
such as PD.

ACKNOWLEDGMENTS
We acknowledge the help of Prof. Maria Stamelou and Prof. Kailash Bhatia.

REFERENCES
Adler, C. H., Dugger, B. N., Hentz, J. G., Hinni, M. L., Lott, D. G., Driver-Dunckley, E.,
et al. (2016). Peripheral synucleinopathy in early Parkinson’s disease: Submandibular
gland needle biopsy findings. Movement Disorders, 31(2), 250–256.
Antonini, A., Odin, P., Kleinman, L., Skalicky, А., Marshall, Е., Sail, K., et al. (2015).
Implementing a Delphi panel to improve understanding of patient characteristics of
advanced Parkinson’s disease. Movement Disorders, 30. Poster No 1186. Presented at
the 19th International Congress of Parkinson’s Disease and Movement Disorders, June
14–18, 2015, San Diego, CA.
194 Nataliya Titova et al.

Beavan, M., McNeill, A., Proukakis, C., Hughes, D. A., Mehta, A., & Schapira, A. H.
(2015). Evolution of prodromal clinical markers of Parkinson disease in a GBA
mutation-positive cohort. JAMA Neurology, 72(2), 201–208.
Biomarkers Definitions Working Group. (2001). Biomarkers and surrogate endpoints: Pre-
ferred definitions and conceptual framework. Clinical Pharmacology and Therapeutics,
69(3), 89–95.
Braak, H., Del Tredici, K., Rub, U., de Vos, R. A., Jansen Steur, E. N., & Braak, E. (2003).
Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiology of Aging,
24(2), 197–211.
Bufalino, C., Hepgul, N., Aguglia, E., & Pariante, C. M. (2013). The role of immune genes
in the association between depression and inflammation: A review of recent clinical stud-
ies. Brain, Behavior, and Immunity, 31, 31–47.
Chahine, L. M., Stern, M. B., & Chen-Plotkin, A. (2014). Blood-based biomarkers for
Parkinson’s disease. Parkinsonism & Related Disorders, 20(Suppl. 1), S99–103.
Chahine, L. M., Weintraub, D., Hawkins, K. A., Siderowf, A., Eberly, S., Oakes, D., et al.
(2016). Cognition in individuals at risk for Parkinson’s: Parkinson associated risk syn-
drome (PARS) study findings. Movement Disorders, 31(1), 86–94.
Chaudhuri, K. R. (2016). Progression and biomarkers for Parkinson disease: Merging motor
with nonmotor symptoms. Neurology, 87(2), 128–129.
Cipriani, S., Chen, X., & Schwarzschild, M. A. (2010). Urate: A novel biomarker
of Parkinson’s disease risk, diagnosis and prognosis. Biomarkers in Medicine, 4(5),
701–712.
Delenclos, M., Jones, D. R., McLean, P. J., & Uitti, R. J. (2016). Biomarkers in Parkinson’s
disease: Advances and strategies. Parkinsonism & Related Disorders, 22(Suppl. 1),
S106–S110.
Diederich, N. J., Pieri, V., Hipp, G., Rufra, O., Blyth, S., & Vaillant, M. (2010). Discrim-
inative power of different nonmotor signs in early Parkinson’s disease. A case-control
study. Movement Disorders, 25(7), 882–887.
Espay, A. J., LeWitt, P. A., & Kaufmann, H. (2014). Norepinephrine deficiency in
Parkinson’s disease: The case for noradrenergic enhancement. Movement Disorders,
29(14), 1710–1719.
Fairfoul, G., McGuire, L. I., Pal, S., Ironside, J. W., Neumann, J., Christie, S., et al. (2016).
Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies. Annals
of Clinical and Translational Neurology, 3(10), 812–818.
Gao, X., Chen, H., Schwarzschild, M. A., Glasser, D. B., Logroscino, G., Rimm, E. B., et al.
(2007). Erectile function and risk of Parkinson’s disease. American Journal of Epidemiology,
166(12), 1446–1450.
Gao, X., Simon, K. C., Schwarzschild, M. A., & Ascherio, A. (2012). Prospective study of
statin use and risk of Parkinson disease. Archives of Neurology, 69(3), 380–384.
Gibbons, C. H., Garcia, J., Wang, N., Shih, L. C., & Freeman, R. (2016). The diagnostic
discrimination of cutaneous alpha-synuclein deposition in Parkinson disease. Neurology,
87(5), 505–512.
Gjerløff, T., Fedorova, T., Knudsen, K., Munk, O. L., Nahimi, A., Jacobsen, S., et al. (2015).
Imaging acetylcholinesterase density in peripheral organs in Parkinson’s disease with
11C-donepezil PET. Brain, 138(Pt. 3), 653–663.
Halliday, G. M., Holton, J. L., Revesz, T., & Dickson, D. W. (2011b). Neuropathology
underlying clinical variability in patients with synucleinopathies. Acta Neuropathologica,
122(2), 187–204.
Halliday, G., Lees, A., & Stern, M. (2011a). Milestones in Parkinson’s disease—Clinical and
pathologic features. Movement Disorders, 26(6), 1015–1021.
Hirsch, E. C., & Hunot, S. (2009). Neuroinflammation in Parkinson’s disease: A target for
neuroprotection? The Lancet Neurology, 8(4), 382–397.
Parkinson’s and Biomarkers 195

Houlden, H., & Singleton, A. B. (2012). The genetics and neuropathology of Parkinson’s
disease. Acta Neuropathologica, 124(3), 325–338.
Jellinger, K. A. (2015). Neuropathobiology of non-motor symptoms in Parkinson disease.
Journal of Neural Transmission (Vienna, Austria: 1996), 122(10), 1429–1440.
Jennings, D., Siderowf, M., Stern, M., & Marek, K. (2013). Evaluating phenoconversion to
PD in the PARS prodromal cohort. Movement Disorders, 29(Suppl), S59–S60.
Kang, S. Y., Ma, H. I., Lim, Y. M., Hwang, S. H., & Kim, Y. J. (2013). Fatigue in drug-naı̈ve
Parkinson’s disease. European Neurology, 70(1–2), 59–64.
Klein, C., & Schlossmacher, M. G. (2007). Parkinson disease, 10 years after its genetic
revolution: Multiple clues to a complex disorder. Neurology, 69(22), 2093–2104.
Kroksveen, A. C., Opsahl, J. A., Aye, T. T., Ulvik, R. J., & Berven, F. S. (2011). Proteomics
of human cerebrospinal fluid: Discovery and verification of biomarker candidates in
neurodegenerative diseases using quantitative proteomics. Journal of Proteomics, 74(4),
371–388.
Lee, Y. C., Lin, C. H., Wu, R. M., Lin, M. S., Lin, J. W., Chang, C. H., et al. (2013).
Discontinuation of statin therapy associates with Parkinson disease: A population-based
study. Neurology, 81(5), 410–416.
Lin, C. H., Wu, R. M., Chang, H. Y., Chiang, Y. T., & Lin, H. H. (2013). Preceding pain
symptoms and Parkinson’s disease: A nationwide population-based cohort study.
European Journal of Neurology, 20(10), 1398–1404.
Mahlknecht, P., Seppi, K., & Poewe, W. (2015). The concept of prodromal Parkinson’s
disease. Journal of Parkinson’s Disease, 5(4), 681–697.
Miller, D. B., & O’Callaghan, J. P. (2015). Biomarkers of Parkinson’s disease: Present and
future. Metabolism, 64(3 Suppl. 1), S40–S46.
Moehle, M. S., & West, A. B. (2015). M1 and M2 immune activation in Parkinson’s disease:
Foe and ally? Neuroscience, 302, 59–73.
Mollenhauer, B., Zimmermann, J., Sixel-Doring, F., Focke, N. K., Wicke, T.,
Ebentheuer, J., et al. (2016). Monitoring of 30 marker candidates in early Parkinson
disease as progression markers. Neurology, 87(2), 168–177.
Pavese, N., & Brooks, D. J. (2009). Imaging neurodegeneration in Parkinson’s disease.
Biochimica et Biophysica Acta, 1792(7), 722–729.
Pavese, N., Metta, V., Bose, S. K., Chaudhuri, K. R., & Brooks, D. J. (2010). Fatigue in
Parkinson’s disease is linked to striatal and limbic serotonergic dysfunction. Brain,
133(11), 3434–3443.
Pavese, N., Simpson, B. S., Metta, V., Ramlackhansingh, A., Chaudhuri, K. R., &
Brooks, D. J. (2012). [18F]FDOPA uptake in the raphe nuclei complex reflects serotonin
transporter availability. A combined [18F]FDOPA and [11C]DASB PET study in
Parkinson’s disease. Neuroimage, 59(2), 1080–1084.
Pellecchia, M. T., Santangelo, G., Picillo, M., Pivonello, R., Longo, K., Pivonello, C., et al.
(2013). Serum epidermal growth factor predicts cognitive functions in early, drug-naive
Parkinson’s disease patients. Journal of Neurology, 260(2), 438–444.
Politis, M., Wu, K., Loane, C., Kiferle, L., Molloy, S., Brooks, D. J., et al. (2010). Staging of
serotonergic dysfunction in Parkinson’s disease: An in vivo 11C-DASB PET study. Neu-
robiology of Disease, 40(1), 216–221.
Postuma, R. B., Gagnon, J.-F., & Montplaisir, J. Y. (2013). REM sleep behavior disorder and
prodromal neurodegeneration—Where are we headed? Tremor and Other Hyperkinetic
Movements, 3. pii: tre-03-134-2929-1.
Sato, S., Mizuno, Y., & Hattori, N. (2005). Urinary 8-hydroxydeoxyguanosine levels as a
biomarker for progression of Parkinson disease. Neurology, 64(6), 1081–1083.
Sauerbier, A., & Chaudhuri, K. R. (2015). Nonmotor symptoms in Parkinson’s disease.
In J. Jankovic, & E. Tolosa (Eds.), Parkinson’s Disease and Movement Disorders
(6th Revised ed.). Lippincott Williams and Wilkins.
196 Nataliya Titova et al.

Sauerbier, A., Jenner, P., Todorova, A., & Chaudhuri, K. R. (2016). Non motor subtypes
and Parkinson’s disease. Parkinsonism & Related Disorders, 22(Suppl. 1), S41–S46.
Savica, R., Grossardt, B. R., Bower, J. H., Ahlskog, J. E., & Rocca, W. A. (2013). Incidence
and pathology of synucleinopathies and tauopathies related to parkinsonism. JAMA Neu-
rology, 70(7), 859–866.
Scheperjans, F. (2016). Can microbiota research change our understanding of neurodegen-
erative diseases? Neurodegenerative Disease Management, 6(2), 81–85.
Schrag, A., Horsfall, L., Walters, K., Noyce, A., & Petersen, I. (2015). Prediagnostic presen-
tations of Parkinson’s disease in primary care: A case-control study. The Lancet Neurology,
14(1), 57–64.
Shannon, K. M., Keshavarzian, A., Mutlu, E., Dodiya, H. B., Daian, D., Jaglin, J. A., et al.
(2012). Alpha-synuclein in colonic submucosa in early untreated Parkinson’s disease.
Movement Disorders, 27(6), 709–715.
Sharma, S., Moon, C. S., Khogali, A., Haidous, A., Chabenne, A., Ojo, C., et al. (2013).
Biomarkers in Parkinson’s disease (recent update). Neurochemistry International, 63(3),
201–229.
Shi, M., Huber, B. R., & Zhang, J. (2010a). Biomarkers for cognitive impairment in
Parkinson disease. Brain Pathology (Zurich, Switzerland), 20(3), 660–671.
Shi, M., Zabetian, C. P., Hancock, A. M., Ginghina, C., Hong, Z., Yearout, D., et al.
(2010b). Significance and confounders of peripheral DJ-1 and alpha-synuclein in
Parkinson disease. Neuroscience Letters, 480(1), 78–82.
Shimada, H., Hirano, S., Shinotoh, H., Aotsuka, A., Sato, K., Tanaka, N., et al. (2009). Map-
ping of brain acetylcholinesterase alterations in Lewy body disease by PET. Neurology,
73(4), 273–278.
Sixel-D€oring, F., Trautmann, E., Mollenhauer, B., & Trenkwalder, C. (2014). Rapid eye
movement sleep behavioral events: A new marker for neurodegeneration in early
Parkinson disease? Sleep, 37(3), 431–438.
Titova, N., Padmakumar, C., Lewis, S. J., & Chaudhuri, K. R. (2016). Parkinson’s:
A syndrome rather than a disease? Journal of Neural Transmission. in press. http://dx.
doi.org/10.1007/s00702-016-1667-6.
Weintraub, D., Simuni, T., Caspell-Garcia, C., Coffey, C., Lasch, S., Siderowf, A., et al.
(2015). Parkinson’s Progression Markers Initiative. Cognitive performance and neuro-
psychiatric symptoms in early, untreated Parkinson’s disease. Movement Disorders, 30(7),
919–927.
Williams-Gray, C. H., Evans, J. R., Goris, A., Foltynie, T., Ban, M., Robbins, T. W., et al.
(2009). The distinct cognitive syndromes of Parkinson’s disease: 5 year follow-up of the
CamPaIGN cohort. Brain, 132(Pt. 11), 2958–2969.