1

Parkinsons Disease

D. Berg . R. Kruger . O. Rie . P. Riederer

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Clinical Manifestation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

5
5.1
5.2

Pathoanatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Histopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Pathoanatomy of the Basal Ganglia in PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

6
6.1
6.2
6.2.1
6.2.2
6.2.3
6.3
6.4
6.5

Factors Contributing to the Pathogenesis of PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Oxidative Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Definition and Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Factors Contributing to the Generation of Oxidative Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Factors Diminishing Oxidative Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Mitochondrial Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Impairment of Calcium Homeostasis and the Role of Glial Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Exotoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Springer-Verlag Berlin Heidelberg 2007

Parkinsons disease

Abstract: The causes for the initiation of neurodegeneration in idiopathic Parkinsons disease (iPD) are
still obscure. However, research of the past decades has shed much light into pathomechanisms involved in
the disease. Defined clinical symptoms, new imaging techniques, and additional functional investigations
allow diagnosis of most PD cases in the course of the disease. Understanding of the pathoanatomy is
essential for realization of the involvement of different brain areas and neurotransmitter systems that
explain the individual development of symptoms. Findings of different factors involved in the pathogenesis
have led to the hypothesis that iPD is a multifactorial disorder. It is hoped that further elucidation of these
and other pathogenetic factors will lead to an earlier diagnosis and allow a more causative, neuroprotective
treatment.
List of Abbreviations: CBGD, corticobasal ganglionic degeneration; CCT, cranial computer tomography;
ILBD, Lewy body disease; iPD, idiopathic Parkinsons disease; MRI, magnetic resonance imaging; MSA,
multiple system atrophy; PD, Parkinsons disease; PSP, progressive supranuclear palsy; SN, substantia nigra;
SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; TCS, transcranial sonography;
UPDRS, Unified Parkinsons Disease Rating Scale

Introduction

With a prevalence of 1:1000, Parkinsons disease (PD) is one of the most common neurological diseases and
the second most common movement disorder. An agedependent increase in incidence is known, affecting
1.4% of the 55year old group and 3.4% of the population of 75 years of age (De Rijk et al., 1997). According to
growing life expectancy, a four times increase in prevalence is expected for the next 20 years in industrialized
countries (World Health Organisation, 1998) posing great medical, social, and economical challenges.
Although the primary pathology and key defects of neurotransmission leading to the clinical picture of
PD are known, the cause of initiation and progression of neurodegeneration in the disease process is still
obscure. However, extensive research has elucidated biochemical alterations of the affected brain areas and
knowledge about a genetic contribution to and molecular biological mechanism of the disease (see chapter by
Kruger et al.) is still growing, giving promising perspectives for future research and therapeutic strategies.

History

The first clinical description of PD was presented by Parkinson in 1817, who believed that the disorder
originated from disturbances in the upper cervical spinal cord. More than 70 years later, Blocq and
Marinesco (1893) discovered the destruction of the substantia nigra (SN) in Parkinsonian patients. The
identification of the typical intracellular and extraneuronal eosinophil inclusions in the dorsal nucleus of
the vagal nerve and the nucleus basalis Meynert in PD patients by Lewy in 1912 was followed by the
discovery of the same inclusion in the SN by Tretiakoff a few years later. These findings initiated further
research on the impact of SN alterations for the clinical manifestation of PD (Tretiakoff, 1919; Hassler,
1938; Greenfield and Bosanquet, 1953) cumulating in two pioneering findings: (i) Carlsson et al. (1957)
realized that dopamine is a neurotransmitter and (ii) Ehringer and Hornykiewicz (1962) described dopamine deficiency in the striatum as the cause for the clinical manifestation of the disease. First administrations of intravenous (Birkmayer and Hornykiewicz, 1961) and oral (Barbeau et al., 1962) dopamine
constituted the basis of the still most effective symptomatic therapy: Substitution of dopamine and
implementation of dopamine agonists. The discoveries that toxins like MPP, derived from the drug
MPTP might lead to the clinical picture of PD with similar histological findings (Davis et al., 1979;
Langston et al., 1983) and that disturbances in the trace metal content like increased iron levels of the SN
may induce and accelerate oxidative stress (Sofic et al., 1988) initiated extensive research on the influence of
exo and endotoxins in disease development. Discovery of monogenetically caused forms of PD (chapter 3
of this book) and elucidation of the underlying pathomechanisms as well as of genetic susceptibility factors
for the disease have now lead to the consensus of multifactorial causes of sporadic PD.

Parkinsons disease

Clinical Manifestation

For the diagnosis of PD it is essential to differentiate between idiopathic or primary PD and secondary
Parkinsonian syndromes. In contrast to idiopathic PD and Parkinsonian syndromes associated with other
neurodegenerative diseases, the etiology of secondary Parkinsonian syndromes is known (> Table 1-1).
These secondary Parkinsonisms need to be excluded as they require different therapeutical strategies.

. Table 1-1
Symptomatic causes for parkinsonian syndromes, also called secondary PD
Diagnosis
Drug induced parkinsonism
Tumors or hydrocephalus
Recurring ischemic insults
Infections, postencephalic
Metabolic causes
Hereditary neurodegenerative disorders
Severe brain traumas
Seldom intoxications
Psychogenic

Indices
Treatment with neuroleptics, other dopamine receptor blockers,
lithium, calciumantagonists, methyldopa
Other focal symptoms, CCT, MRI
Vascular risk factors, stepwise worsening and additional symptoms
History, systemic symptoms
Changes in copper or calcium metabolism
Family history, additional symptoms
History, CCT, MRI
History, systemic symptoms
Remission for longer periods, additional symptoms

Idiopathic PD is characterized by disturbances of voluntary and involuntary movements. Four cardinal

symptoms, usually beginning at one side, can be differentiated: Akinesia, which refers to a slowing of
movement (bradykinesia) and a reduction in amplitude (hypokinesia) that may lead to a complete loss of
voluntary and involuntary movements (akinesia). In the beginning, especially the fine and rapid alternating
movements are affected. Mikrographia occurs and blinking is infrequent. The face lacks expressive mobility
(hypomimea), and speech gets increasingly monotonic. In later stages saliva is not swallowed as fast as it is
produced resulting in siallorrhea. Posture gets increasingly flexed and gait turns slow, shuffling with small
steps and there is reduced movement of arms. A limited capacity to initiate and stop movements leads to
falling. Rigidity due to tonic innervation of agonists and antagonists is usually more pronounced in muscles
that maintain flexed postures and somewhat greater in large muscle groups. The patients notice firmness
and tenseness of the muscles, which is encountered as a ratchetlike resistance to passive movements by the
examiner interrupted by a rhythmical interruption, the cogwheel phenomenon. The permanent stiffness of
muscles often leads to pain, clinically manifesting as lumbago or shoulderarmsyndrome. Resting tremor is
a coarse, rhythmic tremor with a frequency of 35 Hz, electromyographically characterized by bursts of
activity that alternate between opposing muscle groups. It is most often localized in one or both hands with
the typical sign of pillrolling, less frequently in the feet, jaw, or tongue and usually occurs when the limb is
in an attitude of response. It is diminished by voluntary movements and usually disappears when the
limb is completely relaxed, however, the patient rarely achieves this state. Frequently, a fine 78 per/sec
slightly irregular action tremor of the outstretched fingers and hands may also be noted. Usually, later in the
disease process postural instability occurs, which includes the inability of a patient to make appropriate
postural adjustments to tilting or falling as well as the inability to change from the reclining to the standing
position. Impairment of anticipatory and compensatory rigthening reflexes is the cause of these symptoms
leading to retropulsion, propulsion, and festination.
According to the prevalence of these symptoms PD is classified in subgroups like a tremor dominant or
rigidakinetic type. Besides these cardinal symptoms a number of vegetative symptoms like seborrhea,
obstipation, bladder dysfunction, orthostatic dysregulation, as well as somatosensoric disturbances like
impairment of olfaction, color discrimination, and paraestesia may occur. About 40% of PD patients suffer

Parkinsons disease

from a concomitant depression (Cummings, 1992); in 1520% dementia can be recognized (Biggins et al.,
1992). Gastrointestinal and brainstem associated deficits may precede the cardinal symptoms (Przuntek
et al., 2004) in line with the histopathological staging of Braak (Braak et al., 2003, 2004).
Because of the available symptomatic medication, life expectancy of patients with PD is almost normal.
However, with this medication and partly because of this medication later complications may occur. These
include fluctuation of medication effects like wearingoff, endofdoseakinesia and paroxymal onoff
phenomenons as well as LDopainduced dyskinesia manifesting as choreatic peakofdose, biphasic
or off dyskinesias.

Diagnosis

Diagnosis of PD is primarily clinical. According to the cardinal symptoms, a parkinsonian syndrome (PS) is
diagnosed when hypo and bradykinesia are accompanied by at least one of the other cardinal symptoms
rigor, resting tremor, or postural instability. Supporting criteria for idiopathic PD are given in > Table 1-2.
Symptomatic PS (> Table 1-1) must be ruled out. The main diagnostic difficulties occur in the early disease
stages when additional symptoms arguing for an atypical PS (> Table 1-3) cannot be delineated clearly.

. Table 1-2
If three of the supporting criteria are fulfilled diagnosis is clinically reliable
Supporting criteria for the diagnosis of idiopathic PD
Unilateral manifestation and/or persisting lateralization in the course of the disease
Resting tremor
Positive response (at least 30% improvement) to Ldopa treatment
No additional symptoms indicating involvement of other systems for ten or more years

. Table 1-3
Atypical PS
Atypical PS
Parkinsonian multiple system atrophy
(MSAp)
Cerebellar multiple system atrophy
(MSAp)
Progressive supranuclear palsy (PSP)
Cortico basal ganglionic degeneration
(CBGD)
Diffuse Lewy body dementia (DLBD)

Most frequent additional symptoms

Autonomic dysfunction, especially orthostatic hypotension, male
impotence, urinary difficulties, dystonia
Cerebellar signs, pyramidal signs, autonomic dysfunction
Postural instability, vertical gaze palsy, dementia, dysphagia
Cortical signs, alien limb syndrome, myoclonus, pyramidal signs
Dementia, fluctuation of vigilance, early and frequent hallucinations
on dopaminergic treatment

With progression of the disease, however, it needs to be considered that symptoms which in the beginning
of the disease would have been ascribed to an atypical PD like dementia and dystonic postures become
frequent in idiopathic PD. Also, postural instability and autonomic symptoms occur in the majority of
advanced PD cases. Therefore, it is important to document a careful history including age of and symptoms
at onset, duration of the disease, and manifestation of additional symptoms. Response to the symptomatic
medication may also vary as the disease progresses. However, in the beginning there should be a good and

Parkinsons disease

sustained response to dopaminergic agents. If the response to dopaminergic medication is not clear an
Ldopa or apomorphine test should be applied to evaluate therapeutic effects. Severity of PD should be
documented by standardized scales like Hoehn and Yahr (1969) or the Unified Parkinsons Disease Rating
Scale (UPDRS) (Fahn et al., 1987), which is helpful for estimating the individual progression and
complications.
Different methods are useful to rule out symptomatic or atypical PS. Structural neuroimaging techniques
like cranial computer tomography (CCT) or magnetic resonance imaging (MRI) are helpful in ruling out
symptomatic PS like normal pressure hydrocephalus, a frontal tumor, or ischemic lesions. MRI may also be
helpful in the differentiation of the atypical PSs multiple system atrophy (MSA), progressive supranuclear
palsy (PSP), and corticobasal ganglionic degeneration (CBGD) (WarmuthMetz et al., 2001). While normal
MRI weightings of PD patients do not show any diseaserelated abnormalities, there are typical MRI signs
indicating MSAlike diminished T2time signal in the dorsolateral putamen, hyperintense signals at the
border of the lateral putamen, and the external capsule as well as cerebellar atrophy. PSP is characterized
on MRI by lower anteroposterior midbrain diameters, whereas patients with CBGD show a mainly unilateral
pronounced atrophy of the parietal cortex (GimenezRoldan et al., 1994; WarmuthMetz et al., 2001).
As a new, noninvasive and quickly performable method, transcranial sonography (TCS) has become
increasingly important in the diagnosis and differential diagnosis of PD (Becker et al., 1995; Berg et al.,
2001c; Walter et al., 2002). It enables the visualization of the butterflyshaped mesencephalic brainstem as a
normally hypoechogenic structure. In PD, however, hyperechogenic signals can be delineated at the
anatomical side of the SN, which exceed the area of increased echogenicity in the healthy population
(> Figure 1-1). Studies of different groups demonstrated that this echofeature occurring in more than 90%
. Figure 1-1
Transcranial sonography of the mesencephalic brainstem. The butterflyshaped mesencephalic brainstem is
normally hypoechogenic (left). In Parkinsons disease areas of hyperechogenicity (encircled and arrows) may be
displayed on both sides at the anatomical area of the substantia nigra

of patients with idiopathic PD, may also be used to differentiate between idiopathic PD and atypical PS
(Walter et al., 2004; Behnke et al., 2005). Interestingly, this maker indicates a subgroup of the population at
risk for the development of signs of nigrostriatal dysfunction for example, in the process of aging (Berg et al.,
2001d) or under neuroleptic therapy (Berg et al., 2001b). Moreover, it has been shown that increased
echogenicity occurring very early in life in a small proportion of healthy individuals may be associated with
impaired nigrostriatal function detected by 18Fdopa PET (Berg et al., 1999a, 2002). An association between
increased echogenicity and increased iron levels has been established (Berg et al., 1999b, 2002).
Functional neuroimaging methods include Single Photon Emission Tomography (SPECT) and Positron
Emission Tomography (PET) (Thobois et al., 2004). To visualize the presynaptic function, radioactive

Parkinsons disease

markers like 123IFPCIT for SPECT and 18FDopa are used for examinations. Postsynaptically, IBZM
is applied in SPECT examinations to visualize primarily D2 receptors. A number of other radionucleotides like 11CNomifensin, 11CWIN, and 11CDTBZ for presynaptic PET; and 123IbCIT, 123IIPT, and
99m
TCTRODAT1 for presynaptic SPECT studies as well as 11CRacloprid (D2); and 18FDesmethoxy
Fallpyrid (D2) and 11CSch23390 (D1) for postsynaptic PET examinations are only used in specific studies
(Brooks et al., 2003).
The Schellong test, urodynamic examinations, and sympathetic skin response may be helpful to test
for autonomic dysfunction. Electrophysiological investigations like electromyography of the sphincter
muscle and longlatency reflexes may be helpful in the differentiation of atypical PS. Smelling tests are
also used in the differential diagnosis of PS, as more than 80% of patients with idiopathic PD show
alterations in quantitative smelling tests (Katzenschlager and Lees, 2004).

Pathoanatomy

5.1 Histopathology
Idiopathic PD is a multisystem disorder, affecting predisposed nerve cell types in specific regions not only of
the central but also of the peripheral and enteric nervous system. Essential for the neuropathological
diagnosis of PD are alphasynuclein positive Lewy bodies (LB) (> Figure 1-2) and Lewy neurites.
. Figure 1-2
Two Lewy bodies (arrows) in a partly depigmented neuron in the substantia nigra of a patient with Parkinsons
disease (HEstaining) (kindly provided by A. Bornemann, Institute of Neuropathology, University of Tubingen)

LBs are typical but not specific for PD, as they or Lewy bodylike inclusions are also found in other
neurodegenerative diseases like multiple system atrophy, progressive supranuclear palsy, Alzheimers
disease, and other diseases affecting the brain like prion diseases, Down syndrome or subacute progressive
panencephalitis (Lowe et al., 1997; Goedert et al., 1998; Trojanowski and Lee, 2001). More than 25 different
protein components of Lewy bodies are known. One main group of components consists of neurofilaments,
asynuclein, bamyloid, actinlike protein, and many others; another group of proteins is expressed as a
cellular response to the abnormal protein aggregation like ubiquitin, proteasome subunits, and chaperones
(Pollanen et al., 1993; Galvin et al., 1999; Fornai et al., 2003).
In PD, brain areas with the highest levels of asynuclein are those associated with Lewy bodies. It has
therefore been speculated that Lewy bodies result from altered handling of oxidized proteins and may at least
initially represent a protective mechanism of the cell from the toxicity of protein accumulation (Jenner and

Parkinsons disease

Olanow, 1998; Tanaka et al., 2004). Also, the sequestration of toxic iron by Lewy bodies indicates a protective
role of these inclusions (Castellani et al., 2000). New lines of evidence indicate, that by increased expression
even asynuclein itself might protect cells from oxidative stress by inactivation of stresssignaling pathways
(Hashimoto et al., 2002). Some investigations, however, indicate that Lewy bodies might contribute to the
pathological cascade. In analogy to a model with transgenic mice (Tu et al., 1997), it has been hypothesized
that proteins usually transported by axons are accumulated in Lewy bodies leading to a lack of function of
neurons and ultimately to degeneration (Trojanowski, 2001). Moreover, it has been shown that asynuclein
overexpression may contribute to the formation of free radicals, thereby exaggerating the vulnerability of
neurons to dopamineinduced cell death (Turnbull et al., 2001; Junn and Mouradian, 2002). However, it
needs to be noted that the majority of degenerating neurons do not contain Lewy bodies. Therefore, these
inclusions do not seem to be necessary for neurodegeneration (Tompkins and Hill, 1997).
According to the spreading of these histopathological hallmarks of the disease, Braak et al. suggest that
the disease starts at defined sites and advances in a topographically predictable sequence. During the
presymptomatic stages 12 Lewy body pathology is confined to the medulla oblongata with lesions
occurring in the dorsal motor nuclei of the glossopharyngeal and vagal nerves as well as in the olfactory
bulb and nucleus. In the stages 34, the SN and other nuclei of the midbrain and forebrain show increasing
signs of neurodegeneration reaching the anteromedial temporal mesocortex in stage 4. Involvement of
the mature neocortex in the endstages 56 starts with highorder sensory association and prefrontal
areas, followed by firstorder sensory and association/premotor area and primary sensory/motor fields
(Braak et al., 2003, 2004). Most of the leading clinical symptoms can be attributed to degeneration of the
SN. Clinical symptoms usually occur when more than 60% of the dopaminergic cells of the SN have
degenerated (Bernheimer et al., 1973). Neuronal loss occurs in a characteristic distribution affecting
predominantly the ventrolateral and to a lesser extent the medioventral and dorsal parts with a slight
concomitant reactive gliosis and appearance of the characteristic Lewy bodies (Fearnley and Lees, 1991).
The reason why it is the SN, which is the target of the high degree of oxidative stressrelated neurodegeneration in PD, may lie in its high energy metabolism and the high content of dopamine. In the case of the
disease, the dopaminergic cells cannot be protected by the normally huge range of protective mechanisms.
The fact that primarily long fibers with scarce myelinization needing more energy degenerate (Braak et al.,
2003) indicates that a dysbalance of oxidative stress and the physiologically normal lack of antioxidant
capacities of these fibers make them especially vulnerable to neurodegeneration.

5.2 Pathoanatomy of the Basal Ganglia in PD

PD has been recognized as a basal ganglia disorder affecting a multitude of projection areas for a long time.
Specific clinical symptoms could be derived from the physiological function of the basal ganglia like control
of movement amplitude (Desmurget et al., 2004) or reinforcementbased learning (SaintCyr, 2003).
However, the complexity and parallel processing of the information processes have prevented the establishment of a model embracing the underlying pathoanatomy completely. Moreover, altered representation of
different cortical areas as adaptions to the impairments of striatocortical circuits in PD patients renders the
understanding of the circuits involved even more difficult (Kagerer et al., 2003). Still most frequently used is
the basal ganglia model developed by Alexander et al. (1986). Although there is increasing evidence that this
model is not sufficient for all aspects (Foley and Riederer, 2000), it enables a good understanding of the
main pathomechanisms of the disease. According to this model the basal ganglia plays a central role in
integrating and reorganizing information from cortical and subcortical areas. Signals from the cortex,
thalamus, and brainstem nuclei are taken up by the caudate nucleus and dorsal putamen. Within the basal
ganglia the information is processed by feedback mechanisms induced by the SN and pallidum. Either directly
via the monosynaptic striatal pallidal or indirectly via the polysynaptic striatopallidal way information is then
lead to the pallidum and substantia nigra pars reticulata (SNr) and projected via the thalamus to projection
areas outside the basal ganglia. The dopaminergic system of the substantia nigra pars compacta (SNc) as well
as dopaminergic cell groups of the of the SNr project back to the striatum and to the prefrontal cortex.
According to Alexander et al. (1990), there are at least 5 parallel processing basalgangliathalamocortical

Parkinsons disease

feedback circuits to be discerned, projecting to the respective cortical areas including a motor, an oculomotor,
two prefrontal, and a limbic circuit. These circuits maintain the somatotopic organization of movement
related neurons (Herrero et al., 2002). The inhibitory influence in each of these circuits is modulated by two
counteracting systems. In the direct system, activation of the striatum is the source of direct inhibition of the
internal pallidum and SNr, reducing the normally inhibitory influence of these nuclei on the thalamus.
Neurons involved are biochemically characterized by containing mainly D1 dopamine receptors and coexpress the peptide substance P and dynorphin (Steiner and Gerfen, 1998). Contrary, in the indirect system
inhibitory projection to the external pallidum leads via inhibition of the subthalamic nucleus to enhanced
activation of the inhibitory influence of the internal pallidum and SNr resulting in enhanced inhibitory
function of the thalamus. Striatal neurons involved in this pathway express mainly D2 dopamine receptors
and the peptide enkephalin. In PD especially the indirect system is thought to be involved. Diminished
dopaminergic projection of the SNc to the striatum is supposed to result in reduced activation of the
inhibitory influence of this basal ganglia area and to be the causative for many of the clinical symptoms
(Mitchell et al., 1989).
Additionally, the basal ganglia are intimately interconnected with brain stem nuclei like the locus
ceruleus or raphe nuclei (Obeso et al., 2002). Besides, neurodegeneration and Lewy body pathology are
found in many other cortical and subcortical areas involved in these circuits (Braak et al., 1995; Jellinger,
1999). Involvement of the limbic system results in a loss of emotional modulation of movements (Braak
and Braak, 2000) and additional endocrine, autonomic, and mnestic disturbances, when the amygdala are
affected (Braak et al., 1998). When the met and leuencephalin systems, which normally modulate the
dopaminergic system, are affected it leads to further dysregulation of this neurotransmitter. Degeneration
of nuclei involved in the synthesis of other neurotransmitters like noradrenalin (locus ceruleus), acetylcholine (nucleus basalis Meynert), and serotonin (raphe nuclei) leads to symptoms like cognitive decline and
depression (Jellinger, 1999, 2001). Interestingly, vulnerability for neurodegeneration is very selective,
leaving even specific dopaminergic subgroups of the SN unaffected (Braak and Braak, 2000). The reason
for this selective vulnerability is not clear, yet, although there are a number of models referring to known
mechanisms to explain this selective neurodegeneration.

Factors Contributing to the Pathogenesis of PD

Only a small percentage of PD patients suffer from a monogenetically caused disease (chapter 3 of this
book). However, understanding derived from pathomechansims of these genetically determined metabolic
pathways, like disturbance of the ubiquitinproteasome system, have greatly extended knowledge of
possible causes of the disorder, that may also contribute to sporadic PD. The main group of disease cases
seems to be caused by a variable combination of factors including endogenous production of oxidative
stress on the one hand and a variable chronic exposure to environmental agents, in addition to a genetic
vulnerability. These factors may influence gene expression in the substantia nigra (Grunblatt et al., 2004).
Extensive research of the past years has discovered some main factors contributing to the pathogenetic
cascade of the disease.

6.1 Aging
One of the main risk factors for sporadic PD is aging. It has been estimated that 10,000 oxidative
interactions occur between DNA and endogenously generated free radicals per human cell per day, and
that in older animals at least one of every three proteins in the cell is dysfunctional as an enzyme or
structural protein, due to oxidative modification, indicating a key role of free radicals in the process of aging
(Poon et al., 2004). Consequences of this agingrelated oxidative modifications are increased levels of lipid
peroxidation metabolites (Weisser et al., 1997; Volchegorskii et al., 2004) and a reduction in cytoprotective
mechanisms, like decreased levels of hyaluronic acid, which is known to inhibit expression of proinflammatoric cytokines. In addition agingrelated changes in the synthesis and metabolism of neurotransmitters

Parkinsons disease

and their receptors, like a reduction in the density of dopamine receptors (Rinne et al., 1990) in contrast to
an increase in serotonergic receptors (Marcusson et al., 1984) or changes in the metabolism of essential
heavy metals like iron (Zecca et al., 2001) may induce or accelerate pathological cascades of neurodegeneration. The time of manifestation of clinical symptoms seems to depend on the genetic constellation of each
subject, which is responsible for the increased vulnerability to each of these factors.
However, PD can not be explained as an accelerated process of aging. While there is a selective
degeneration of dopaminergic neurons of the SNc in PD, aging is accompanied by loss of dopaminergic
neurons of the dorsal tier of the SN (Fearnley and Lees, 1991; Halliday et al., 1990). Moreover, aging is not
accompanied by the formation of Lewy bodies, the pathologic hallmark of PD.

6.2 Oxidative Stress

6.2.1 Definition and Findings
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated as a result of normal
metabolism. However, the deleterious condition termed oxidative stress (OS) occurs when ROS or RNS


such as the superoxide radical O

2 , nitric oxide (NO) and especially the hydroxyl radical ( OH) due to an
excessive production or diminished decontamination overwhelm the protective defense mechanisms of a
cell resulting in functional disruption and ultimately in cell death.
Although it is no question that OS it as key event in the neurodegenerative process of all forms of PD
(Berg et al., 2004), it is not clear, yet, whether it constitutes a primary event or a consequence of other
pathogenetic factors. Studies in patients with incidental Lewy body disease (ILBD), the supposed presymptomatic form of PD, implicated that there is no conclusive evidence of markers of OS at an early stage
of neurodegeneration besides a reduction in GSH levels (Jenner, 2003). However, only few samples have
been examined with tissue homogenates rather than detailed studies on dopaminergic neurons. Therefore,
no final conclusion can be derived from this observation. On the other hand, it has been shown that
oxidative dimer formation constitutes the critical ratelimiting step for fibrillogenesis of asynuclein,
providing an explanation that overproduction of ROS and/or impairment of cellular antioxidative mechanisms could be a primary event both in the initiation and in the progression of PD (Krishnan et al., 2003).
Because of their high reactivity free radicals cannot be measured directly. However, there are a number
of indices for OS and its deleterious consequences in the SN of PD patients:

Lipid peroxidation of membranes Membranes are crucial for cell viability. As a consequence of OS
reaction of fatty acids of polar lipids with oxygen or a reaction catalyzed by either metals like iron or by
NADPH cytochrome P450 reductase leads to the formation of free radical intermediates and semistable peroxide. Chemically and metabolically stable oxidation products like isoprostanes and increased
levels of secondary products like conjugated dienes, hydrocarbon gases (e.g., ethane) and carbonyl
compounds (e.g., malondialdehyde), and decreased levels of polyunsaturated fatty acid can be
measured (Dexter et al., 1989; Practico, 2001; Montine et al., 2004).

Oxidation of proteins ROS may directly oxidize amino acids leading to a loss of function of proteins and
a deactivation of enzymes (Stadtman, 2001). Increase in malondialdehyde has been suggested to lead to
intra and intermolecular crosslinks of proteins (Goetz and Gerlach, 2004). Moreover, conformational
changes and adducts of lipid peroxidation (Marnett, 2000) may result in aggregation or precipitation
of undegradable proteins, a hypothesis that is underlined by the detection of OSdependent protein
aggregation in the form of advanced glycation end products (Munch et al., 1999) which are already
detectable within Lewy bodies, when no clinical sign of PD is obvious (Munch et al., 2000).

DNA damage caused by ROS Increased levels of 8hydroxy20 hydroxyguanine, and thymidine glycol in
the SN and striatum of Parkinsons disease brain indicate DNA base damage (SanchezRamos et al.,
1994; Alam et al., 1997; Poon et al., 2004) as a result of strand breakage, nucleic acidprotein crosslinking, and nucleic base modification by ROS. These processes also affect the mitochondrial DNA
(mtDNA), which is transiently attached to the inner mitochondrial membrane where a large amount of
ROS is produced (Goetz and Gerlach, 2004).

10

1

Parkinsons disease

Further markers of OS 3Nitrotyrosine, the marker of OS induced by peroxynitrite, has been detected
in Lewy bodies (Giasson et al., 2000). Decreased levels of reduced glutathione in the SN of PD (Sofic
et al., 1992) and low activity of phospholipidcatabolising enzymes in normal SN compared with other
regions of the human brain, indicate a reduced repair capacity of oxidative damage (Ross et al., 1998).
On the other hand upregulation of antioxidant enzymes like Mndependent superoxide dismutase and
nonselenium glutathione peroxidase has been described (Martilla et al., 1988; Yoshida et al., 1994;
Power et al., 2002).

Very importantly, the 3040% changes in parameters of oxidative stress found in homogenates of nigral
tissue cannot be restricted to the dopaminergic cells accounting for only 12% of the whole nigral cell
population (Jenner, 2003). It needs to be considered that changes occur also in other cell types, predominantly in glial cells, implying a concept of general metabolic failure in the SN of PD patients.
Moreover, peripheral markers for oxidative stress indicate a possible systemic affection related to the
oxidative stress in the brain. These include altered SOD activity, reductions in glutamate uptake, increased
levels of malondialdehyde as well as thiobarbituric acid reactive substances detected in erythrocytes, serum, and
plasma of PD patients and primary and oxidative DNA damage in lymphocytes of untreated Parkinson patients
(Bostantjopoulou et al., 1997; Nagatsu et al., 1999; Ferrarese et al., 2001; Serra et al., 2001; Migliore et al., 2002).

6.2.2 Factors Contributing to the Generation of Oxidative Stress

A number of factors are known to exert toxic influences in neurodegenerative diseases (for details see the
chapter by Gerlach and Double). For the generation of oxidative stress in PD some factors have been shown
to be responsible.
1. Dopamine Metabolism of this main neurotransmitter of the neurons degenerating in PD produces
ROS and might therefore account at least in part for the selective vulnerability of the SNc. Already
during the process of dopamine synthesis cytotoxic products like reactive dopamine quinone products
may be formed (Choi et al., 2003). Then, autooxidation leading to the production of dopaquinone and
O

2 (Lotharius and Brundin, 2002) or enzymatic metabolism forming H2O2, which is converted into


OH via the ironmediated Fenton reaction (Gotz et al., 1994; Maruyama and Naoi, 2002) are the main
sources of ROS derived from dopamine metabolism. Moreover, dopamine and various of its metabolites can inhibit complex I of the electrontransport chain (see later). An additional toxic effect of the
antiparkinsonian drug LDopa has been the matter of discussion for many years. In vitro experiments
seem to indicate an increase in OS and neurodegeneration after LDopa administration (Spencer et al.,
1994; Walinshaw and Waters, 1995). In animal experiments, however, no increased toxicity was seen
after LDopa application (Perry et al., 1984). Also, the ELLDopa clinical trial has not substantiated an
LDopainduced toxicity (Fahn, 1999).
2. Transition metals iron, copper, and manganese By their ability to undergo oneelectron transfer, these
essential metals are also potentially dangerous, enabling autooxidation (e.g., of dopamine and ascorbate), conversion of H2O2 to (HO)
, or decomposition of lipid peroxides to reactive peroxyl and
alkoxyl radicals. Most evidence exists for the contribution of iron to OS in PD. Iron content of the basal
ganglia and SN is already under physiologic conditions higher than in most other regions of the brain
(Hallgren and Sourander, 1958). This is important, as iron is required as a cofactor for the synthesis of
dopamine by the enzyme tyrosine hydroxylase. The physiologically high iron content of the SN is even
35% higher in PD, with an elevation of the Fe(III)/Fe(II)ratio from 2:1 to almost 1:2 (Riederer et al.,
1985, 1988, 1989; Sofic et al., 1988; Dexter et al., 1993; Gerlach et al., 1994). Increased levels of iron and
Fe(II) enhance the conversion of H2O2 to
OH via the Fenton reaction and favor a greater turnover in
the HaberWeiss cycle, which leads to an amplification of ROS (Riederer and Youdim, 1993; Berg et al.,
2001a) with all detrimental consequences. Moreover, by catalyzing oxidative reactions iron enhances
the conversion of unfolded or ahelical conformation of asynuclein to bpleated sheet conformation,
the primary form in Lewy bodies (Hashimoto et al., 1998; Munch et al., 2000; Golts et al., 2002). It is
not entirely clear yet, at what time in the pathophysiological cascade of PD iron accumulation occurs.

Parkinsons disease

3.

4.

Data from recent transcranial ultrasound studies also imply iron accumulation to occur very early in
the disease process, constituting a rather primary cause of the disease(Becker et al., 1995; Berg et al.,
1999a, 2002). Continuous and unlimited iron uptake through a disturbed bloodbrain barrier may be
one reason for the accumulation (Riederer, 2004; Kortekaas et al., 2005). Moreover, an association of
sequence variations in some genes encoding for iron metabolizing proteins within the brain and PD has
been established (Borie et al., 2002; Hochstrasser et al., 2004).
Neuromelanin This excellent chelator of metal ions, especially iron (BenShachar et al., 1991), has
been discussed to be neuroprotective (Gerlach et al., 1994). However, it seems that the amount of iron
determines the role of NM: In the situation of normal iron levels, this redox active metal is sequestered.
In the presence of excess iron, however, NM promotes the formation of reactive oxygen species and
fosters the release of iron into the cytoplasm (Zareba et al., 1995; Zecca et al., 1996; Double et al., 1999).
Additionally, NM can bind a variety of potentially toxic substances like MPP, the neurotoxic
metabolite of MPTP or pesticides suggesting a contribution to neurotoxinmediated neurodegeneration (DAmato et al., 1986; Gerlach et al., 1994).
Nitric Oxide Nitric oxide (NO) is produced in the reaction of arginine with molecular oxygen to
generate citrulline and NO (Bredt, 1999). In PD enhanced production of NO by activated glial cells has
been observed (Hunot et al., 1999). As a free radical, NO contributes to OS by reacting with proteins
and lipids (Beckmann, 1996; Iravani et al., 2002). Additionally, highly reactive intermediates like
peroxinitrite are formed in the presence of superoxide, inducing DNA damage and lipid peroxidation
(Liu et al., 2002). NO also mediates iron release from ferritin (Reif and Simmons, 1990) and interacts
directly with the respiratory chain (Antunes et al., 2002).

6.2.3 Factors Diminishing Oxidative Stress

The cell protects itself against oxidative damage using either enzymatic reactions by superoxide dismutase
(SOD), glutathione peroxidase, or catalase, or interaction with substances binding the toxic metabolites like
the antioxidants vitamin C and E, glutathione (GSH), cystein, or coenzyme Q (Gerlach et al., 2001).
However, although expected to counteract the increased oxidative stress no difference in the levels of
antioxidative vitamins was found between PD patients and controls (Riederer et al., 1989). For catalase and
glutathione peroxidase almost equal or only slightly reduced levels and activities were found (Ambani et al.,
1975; Kish et al., 1985; Sian et al., 1994). However, increase in the antioxidant nonselenium glutathione
peroxidase in astrocytes in PD brains (Power et al., 2002) and a specific and unique increase in SOD in the
SNc were detected (Martilla et al., 1988; Yoshida et al., 1994). However, this increase is not accompanied by
an increase in the subsequent enzymes of the detoxification process. As H2O2 is generated in the process of
detoxifying free radicals by SOD, lack of the enzymes catalase and glutathione needed for further conversion
leads to a deleterious increase in H2O2 (Foley and Riederer, 1999). Moreover, a reduction of total and
reduced GSH, a very important antioxidant synthesized in every brain cell (Wu et al., 2004), is detectable in
the SNc in PD (Riederer et al., 1989; Sofic et al., 1992) in the very early pathogenetic process, rendering
neurons more vulnerable to endo or exotoxins (Jenner and Olanow, 1996). Especially for PD GSH
depletion has been shown to cause a cascade of deleterious events like promoting the formation of defective
proteins and thereby impairing the normal ubiquitinproteasome pathway of protein degradation (Bharat
et al., 2002). Additionally, release of arachidonic acid by GSH depletion may cause cellular damage through
its metabolism by lipooxygenase (Kramer et al., 2002; Mytilineou et al., 2002). GSH depletion may also have
an inhibitory affect of mitochondrial complex I activity (Bharat et al., 2002).

6.3 Mitochondrial Dysfunction

Activity of complex I, the first of five complexes of the mitochondrial respiratory chain, has been found to
be reduced by about 30% in SNc of PD patients (Mizuno et al., 1989; Reichmann and Riederer, 1989;

11

12

Parkinsons disease

Janetzky et al., 1994). Decline of complex I activity does not only lead to reduced ATP production resulting
in decreased energy for the cell. Also, less NAD is formed from NADH with the consequence of an
impairment of proton pumping and electron transport, which in turn leads to an increase in reactive
oxygen species, proteasome inhibition, and cell death (Reichmann et al., 1993, Betarbet et al., 2000;
Liu et al., 2002). In addition to the cellular energy supply, the specific role of determining survival
and death in apoptosis induced by endogenous neurotoxins, which has been attributed to mitochondria
(Naoi et al., 2000, 2002), is also impaired by the reduced activity. It is not clear, yet, whether complex I
impairment is a secondary phenomenon for example, resulting from radical formation. On the other hand,
sequence variations in the mitochondrial genome in the brain of PD patients with an increase in number
and variety of mtDNA deletions/rearrangements compared to patients with other movement disorders
or agematched controls (Gu et al., 2002) and a variety of amino acid variations detected in cytochrome b
of the mitochondrial genome in PD patients compared to only few variations in centenarians (Tanaka,
2002) argue for a primary contribution. Besides an additional impairment of complex IV activity (Itoh
et al., 1997) no alterations in the functions of the other complexes of the respiratory chain have been
detected, yet.

6.4 Impairment of Calcium Homeostasis and the Role of Glial Cells

Increase in ROS, overstimulation of a cell by excitotoxic inputs, and impairment of the respiratory chain
may lead to an increase in intracellular calcium. Excitotoxicity means excitatory and toxic properties of a
substance at the same time. Impaired calcium homeostasis with high levels of intracellular calcium may lead
to uncontrolled stimulation of various calciumdependent enzymes and stimulation of mitochondrial
generation of ROS (Gerlach et al., 1996; Starkov et al., 2002). Moreover, calcium overload may uncouple
mitochondria leading to a further enhancement of OS. Because of their need of high rates of energy,
dopaminergic neurons are especially vulnerable to these processes. Moreover, studies on calcium binding to
asynuclein suggest that calcium ions may on the one hand participate in normal asynuclein functioning,
while on the other hand exercising pathological effects known to be involved in Lewy body formation
(Nielsen et al., 2001).
The release of glutamate, the main excitatory transmitter in human central nervous system, is among
others mediated by cytokines (Mogi et al., 1994; Hunot et al., 1999) produced by activated glia cells
(McNaught and Jenner, 2000; Koutsilieri et al., 2002) that lead to an elevation of OS (Gao et al., 2002) and
excitotoxicity. However, activation of glial cells does not only exert detrimental influences on dopaminergic
neurons (Teismann and Schulz, 2004). They also produce glutathione peroxidase and pyruvate, which
protect cells from highly toxic free radicals (Damier et al., 1993; Desagher et al., 1997), and neurotrophic
factors exerting a neuroprotective influencelike GDNF (glial cell linederived neurotrophic factor) and
BDNF (brainderived neurotrophic factor), which have proven neuroprotective against different neurotoxic
substances in vitro and in vivo (Beck et al., 1993; Gash et al., 1996).

6.5 Exotoxins
Since the discovery that MPTP, an impurity formed during the preparation of meperidine, provokes severe,
progressive parkinsonism (Davis et al., 1979; Langston et al., 1983), many epidemiological studies have
focussed on the possible contribution of environmental factors, nutritional components, or exposition to
certain toxins to the pathogenesis of PD. So far, substances known to cause or promote PD are CO,
manganese, cyanid, and methanol (Glass 1983; Zayed et al., 1990). Exposition to these substances might be
at home, as seen in the case of drinking water from wells, polluted with heavy metals (Rajput et al., 1986;
Barbeau et al., 1987). However, not all investigations corroborate these findings (Rajput et al., 1987). At work
pesticides and herbicides are discussed to be the main substances of exposition (SanchezRamos et al., 1987;
Sechi et al., 1992; Sherer et al., 2002a; McCarthy et al., 2004). Chronic treatment with the insecticide rotenone,
a specific inhibitor of complex I, has been suggested to cause delayed oxidative stress (Sherer et al., 2002b;

Parkinsons disease

Hoglinger et al., 2003). Other toxins like chloral hydrate or 1trichloromethyl1,2,3,4tetrahydrobetacarboline reacting with endogen amines (Bringmann et al., 2000; Riederer et al., 2002) and dieldrin (Kitazawa et al.,
2001) are still investigated. As not all individuals exposed to the same environmental toxins develop PD, a
genetically determined susceptibility is probable (see earlier; Jenner, 2001; Tsang and Soong, 2003).
The time point of exposure may be variable. Interestingly, there are indices that environmental factors,
including viral and risk factors already associated with pregnancy and birth, together with genetically
determined lability may increase the incidence of early hypokinesia and parkinsonism in particular and of
Parkinsons disease in later life by disturbing the immature basal ganglia at critical developmental stages
(Riederer and Foley, 2002; Iova et al., 2004).
Taken together, research of the past decades has elucidated many aspects concerning the pathoanatomy,
histology, and some risk factors for PD. However, although some of the basic pathomechanisms for
neuronal death in PD have been elucidated, the initial cause and reason for progression are still not entirely
understood. Many helpful aspects concerning possible pathomechanisms have been revealed by insights
derived from studies in monogenetically caused forms of the disease (see chapter 3 of this book).
Together with the understanding of the pathophysiology of the disease, methods for an earlier, in the
best case preclinical diagnosis, need to be developed to enable the ingenious application of neuroprotective
therapeutic strategies (chapter 6 of this book).

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