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Chapter 1

Parkinson’s disease

“I have seen one, who was able to run, but not to walk. I ordered him a grainof opium a day in the gum pill; and in three or four days the shaking hadnearly left him”

Parkinson.

1.1 GeneralParkinson’s disease, first described as the ‘paralysis agitans’ or ‘shaking palsy’ byJames Parkinson over two hundred years ago, has three compelling features. First,one would think that the striking visible signs that characterise this movementdisorder would manifest after a degeneration of many neurones across widespreadregions of the brain. On the contrary, the main zones of pathology of the disease arerather discrete, within distinct neuronal groups lying mainly within the brainstem.Second, despite the disease affecting only about 1% of people, and even then mostare over the age of 50 years, it has been at the forefront of medical science researchand community awareness. This level of prominence may be reflective of severalfactors, that a number of public figures have had the disease or various forms of it,and/or, that it is a disease characterised, for the most part, by an active cognitivemind imprisoned in a dysfunctional body. The fear of losing control of one’sfreedom of movement, and being aware of it, is a terrifying prospect for mostindividuals. Finally, the disease is relentlessly progressive and most forms areinsidious.

In terms of therapeutic treatment of the disease, there is a mixed bag. The currentconventional therapies, on the one hand, are very effective (at least initially) atreducing the motor signs, but they do not reliably stop or even slow the progressionof the disease. The target neurones continue to die relentlessly during the course ofthe treatment. Even after over two hundred years, and so much research andscrutiny, there is still no effective therapy that arrests the disease progression andenhances the survival of neurones in Parkinson’s disease patients. Such a therapy,

doi:10.1088/2053-2571/ab2f70ch1 1-1 ª Morgan & Claypool Publishers 2019

one that alters the course of the disease and increases neuronal survival, has beenreferred to as disease-modifying or neuroprotective. The discovery of an effectiveone remains the so-called holy grail or ‘golden ark of the covenant’ of treatments forpatients with Parkinson’s disease, a priceless treasure that has yet to be discovered bythe ‘Indiana Jones’ of neuroscience researchers.

1.2 Signs and symptomsParkinson’s disease has distinct cardinal motor signs of akinesia (i.e. difficulty ininitiating and stopping movement) and/or bradykinesia (i.e. slowness of movement),lead-pipe rigidity (i.e. increased muscle tone), resting (i.e. pill-rolling) tremor and, asthe disease progresses, postural instability (figure 1.1: Bergman and Deuschl 2002,Jankovic 2008, Helmich et al 2012, Kalia and Lang 2015, Magrinelli et al 2016,French and Muthusamy 2018). There are also associated motor signs of impairedfacial movements (i.e. hypomimia) and fine motor skills (e.g. micrographia), flexedposture, cog-wheel rigidity (i.e. ratchet-like start-stop movements), dysarthria (e.g.softness of voice), dysphagia (i.e. trouble swallowing), festinant (i.e. shuffling) gaitand freezing (i.e. motor block; figure 1.1: Bergman and Deuschl 2002, Jankovic2008, Kalia and Lang 2015).

In addition to these motor signs, there are a number of key non-motorsymptoms associated with the disease. These include cognitive impairment anddementia, psychiatric issues (e.g. depression and anxiety), fatigue, anosmia (i.e.olfactory impairment), rapid-eye movement sleep behaviour disorder (e.g. exces-sive sleepiness, sleep attacks, insomnia, increase in nightmares), gastrointestinaland autonomic dysfunction (e.g. constipation and urogenital dysfunction) andsomatosensory disturbances (e.g. paraesthesia and chronic pain) (figure 1.1: Khooet al 2013, Cosgrove et al 2015, Poewe et al 2017). Usually, patients develop manyof the non-motor symptoms first (referred to as premotor or prodromal phase), forexample, constipation, fatigue, anosmia or depression, followed subsequently bythe motor signs of bradykinesia, rigidity and/or tremor (Jankovic 2008, Helmichet al 2012, Kalia and Lang 2015, Magrinelli et al 2016).

Initial diagnosis of Parkinson’s disease is made when a patient displays any two ofthe cardinal motor signs, with at least one of the two being tremor or bradykinesiaand a positive response to dopamine replacement drug therapy; diagnosis can beconfirmed later with a particular pattern of pathology at post-mortem (see sectionsbelow on pathophysiology and current treatments). The onset is commonlyunilateral, becoming bilateral at later stages. Even so, asymmetry persists through-out the disease (Poewe et al 2017). A typical feature of the disease is that the motorsigns get worse over time and new ones are often added (Bergman and Deuschl 2002,Jankovic 2008, Helmich et al 2012, Kalia and Lang 2015, Magrinelli et al 2016,French and Muthusamy 2018).

Within these main sets of clinical signs and symptoms, there are heterogeneities,with several sub-types of Parkinson’s disease being evident. Patients can displaymotor signs in different combinations and to different extents. There are, forexample, tremor-dominant forms of the disease, whether resting or postural,

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together with bradykinesia–akinesia-rigidity-dominant forms. The tremor-dominantforms tend to follow a more benign disease course than the bradykinesia–akinesia-rigidity-dominant forms (Bergman and Deuschl 2002, Jankovic 2008, Kalia andLang 2015). Most forms of the disease are late-onset, where patients are diagnosedafter 50 years of age, but there are the rarer early-onset forms also, and these tend tobe tremor-dominant and slower in development (Jankovic 2008, Helmich et al 2012,Kalia and Lang 2015, Magrinelli et al 2016). In addition to these clinicalheterogeneities, there are also different genetic and pathological forms of thedisease, all contributing to a varied phenotype (see sections below on pathophysi-ology and risk factors).

Figure 1.1. The constellation ‘the halo’ of signs and symptoms of Parkinson’s disease. Motor signs are in blueand non-motor symptoms, often prodromal, in red. The * denotes the cardinal signs.

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In general, Parkinson’s disease is not fatal. Individuals will not necessarily diefrom it, but instead, their death may occur as a result of afflictions associated with it.For instance, given the motor impairments associated with the disease, falls presenta serious issue for patients at later stages. Further, the dysphagia suffered by manypatients could lead to choking and pulmonary aspiration, while their lack of overallmovement may result in the formation of blood clots and pulmonary embolisms, aswell as pneumonia (Kalia and Lang 2015, Magrinelli et al 2016). In terms of lifeexpectancy, it is, on the whole, a little lower for Parkinson’s disease patients than forthe general population. This is particularly the case for the early-onset cases, wherethe average age of death is approximately twelve years lower than the averagefor the general population, while for the late-onset cases, it is only about three yearslower (Ishihara et al 2007).

1.3 The basal gangliaClassically, the term basal ganglia has been used to describe a group of fiveinterconnected nuclei located in the forebrain and midbrain: the striatum (caudateand putamen), globus pallidus (internal and external segments), substantia nigra(pars compacta (SNc) and pars reticulata (SNr)) and the subthalamic nucleus. Inmore recent times, two other nuclei have been included in the basal ganglia family,namely the zona incerta and pedunculopontine tegmental nucleus (figure 1.2: Parent1996, Blandini et al 2000, Pahapill and Lozano 2000, Bergman and Deuschl2002, Nandi et al 2002a, 2002b, Mitrofanis 2005, Plaha et al 2006, French andMuthusamy 2018).

In the section that follows, aspects of the basic structure, neurochemistry andconnectivity patterns of each nuclei of the basal ganglia will be considered.Following this, there will be an outline of the overall function and more detailedcircuitry of these nuclei.

1.3.1 Basic structure, neurochemistry and connections

1.3.1.1 Striatum: caudate and putamenThe striatum is made up of two functionally similar nuclei, the caudate and putamen(figure 1.2). These nuclei have a common embryological origin and are composedmainly (∼95%) of medium-sized spiny projection cells that use γ-aminobutyric acid(GABA: inhibitory) as a neurotransmitter (figure 1.2). They have been called spinybecause their dendrites are covered in small and thin spinous processes (Parent 1996,Blandini et al 2000). One group of these GABAergic spiny projection neuronescontains substance P and dynorphyn while another contains enkephalin (figure 1.2).The striatum also contains several types of aspiny interneurones, containing eitheracetylcholine, somatostatin, nitric oxide or GABA co-expressing with parvalbuminor calretinin (Parent 1996, Blandini et al 2000). In general, striatal projectionneurones may have one of two types of dopamine receptor, D1 and D2 (Parent 1996,Blandini et al 2000). When dopamine is bound to the D1 receptor, a secondmessenger-signalling cascade is initiated, resulting in depolarisation (i.e. excitation)of the neurone. D1 receptors have been found mainly on GABAergic spiny cells that

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contain substance P. When dopamine is bound to D2 receptors, a second messengercascade results in neuronal hyperpolarisation (i.e. inhibition). D2 receptors are foundmainly on GABAergic spiny cells that contain enkephalin (Parent 1996, Blandiniet al 2000). Most authorities consider the striatum a primary input nucleus of thebasal ganglia, receiving extensive excitatory glutamatergic inputs from the cerebralcortex, amygdala and intralaminar nuclei of the thalamus, as well as dopaminergicones from the SNc. In terms of outputs, the striatum forms distinct projections to theglobus pallidus and the substantia nigra complex only. These particular connectionsof the striatum form clear subdivisions within the nucleus, namely the sensorimotor,associative and limbic zones (Parent 1996, Blandini et al 2000).

Figure 1.2. Schematic diagram of a coronal section showing the location of the basal ganglia nuclei (inCAPITALS) and the cortex and thalamus in the forebrain and brainstem. The purple arrow indicates acortical–basal ganglia–thalamic–cortical loop. The contributions of the substantia nigra, zona incerta andpedunculopontine tegmental nucleus to the loop are not shown. The red box in the brain section of (B)indicates the approximate region of schematic (A).

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1.3.1.2 Globus pallidusThis nucleus is found medial to the putamen and lateral to the white matter of theinternal capsule (figure 1.2). There are two distinct segments, a lateral, external(GPe) and a medial, internal (GPi) segment (Parent 1996, Blandini et al 2000). Bothsegments house GABAergic neurones with large ovoid somata with smooth sparselybranched dendrites (figure 1.2). The globus pallidus receives projections from thestriatum and the subthalamic nucleus, with less prominent inputs arising from SNc,pedunculopontine tegmental nucleus, cortex and thalamus (Parent 1996, Blandiniet al 2000). The inputs from the striatum and subthalamic nucleus have been shownto converge on to the same pallidal neurones. Further, the subthalamic afferentshave been suggested to influence a larger collection of pallidal neurones than thestriatum; the latter projection appears more specific, terminating on a smaller, selectgroup of pallidal neurones (Parent 1996, Blandini et al 2000). The subthalamicprojections are excitatory glutamatergic while those from the striatum are inhibitoryGABAergic. In addition to the inputs from the striatum and subthalamic nucleus,there is a small dopaminergic input from the SNc (Parent 1996, Blandini et al 2000).Although the inputs to the GPe and GPi described above are similar, their outputsare very different. The GPe has projections to the substantia nigra complex,striatum, thalamic reticular nucleus, subthalamic nucleus and GPi, while the GPiprojects to the ventral, mediodorsal and intralaminar thalamic nuclei, lateralhabenular nucleus, midbrain and pontine reticular formations, back to the GPe,putamen and pedunculopontine tegmental nucleus (Parent 1996, Blandini et al2000). Collectively, if the striatum forms the major input zone of the basal ganglia,the globus pallidus, along with the SNr, form the major output zone.

1.3.1.3 Subthalamic nucleusThe subthalamic nucleus is located inferior to the thalamus at the junction with themidbrain (figure 1.2). The somata of the subthalamic neurones are spindle-shaped,pyramidal, or round and have many branching processes (Parent 1996, Blandiniet al 2000). All the subthalamic neurones are glutamatergic (figure 1.2), and thenucleus is considered to be rudimentary in rodents, but well-developed in primates.The nucleus receives inputs from the motor cortex, globus pallidus, pedunculopon-tine tegmental nucleus, midbrain raphe nuclei, and the locus coeruleus (Parent 1996,Blandini et al 2000). The main outputs of the subthalamic nucleus reach the GPi, butthere are also smaller projections to both the GPe and SNr, and even smaller onesstill to the SNc (Parent 1996, Blandini et al 2000). The outputs of the subthalamicnucleus have been shown to influence the initiation of movement by modifying thephysiological settings, such as membrane potentials, of the pallidal and substantianigra neurones prior to the arrival of striatal signals (Parent 1996). The subthalamicnucleus may be divided into three major territories. First, the sensorimotor territoryoccupies the large dorsolateral region of the nucleus. In this region, the subthalamicneurones change discharge rate during movements and in response to somatosen-sory stimulation. Second, the associative territory occupies a small ventromedialregion of the nucleus. Neurones here are activated during visual oculomotor tasks.Third, the limbic territory occupies the medial tip of the nucleus. This region receives

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inputs from limbic cortex and globus pallidus. In primates, these territories involvedistinct neuronal groups, while in rats, individual neurones tend to have multipleprojection sites (e.g. to globus pallidus and SNr), so segregation is less clear (Parent1996, Blandini et al 2000).

1.3.1.4 Substantia nigraThis nucleus lies inferior to the subthalamic nucleus (figure 1.2) and dorsal to thecerebral peduncle and extends the entire length of the midbrain. It is divided into twomain zones: the SNc, a region of densely packed neurones that contain melaninpigments and the SNr a region that is comparatively cell-poor within a dense fibrenetwork of white matter fibres. The SNc contains dopaminergic neurones (figure 1.2)that express tyrosine hydroxylase, the rate limiting enzyme in the production ofcatecholamines (Rinne 1993, Parent 1996, Blandini et al 2000). The SNc can befurther divided into dorsal and ventral sectors based on the density of neurones,chemoarchitecture and the orientation of their dendrites (Parent 1996, Blandini et al2000). For example, the dorsal sector contains fewer neurones and mediolaterallyoriented dendrites; this sector merges with the more medial ventral tegmental area.The ventral sector is more densely populated with neurones whose dendrites areoriented dorsoventrally; further, unlike the dorsal sector and ventral tegmental area,these neurones do not contain calbindin and are more heavily pigmented (seeFitzpatrick et al 2005). The intensity of pigmentation is greatest in primates, withhumans having the heaviest pigmentation (Braak and Braak 1986). Although thereis some disagreement, most authors agree that there are two types of cells in the SNc;a population of small neurones thought to be interneurones and a larger populationof medium- to large-sized neurones thought to be the dopaminergic projectionneurones (François et al 1984). In rodents, the smaller neurones make up ∼10% ofthe SNc and ∼40% of the neurones in the SNr (Gulley and Wood 1971). Unlike theSNc, the bulk of the neurones in the SNr are GABAergic (figure 1.2). The SNc andSNr receive a large topographic input from all regions of the striatum and from thecerebral cortex (Parent 1996, Blandini et al 2000). The GABAergic cells of the SNrproject mainly to the thalamus, the superior colliculus and PpT, while thedopaminergic cells of the SNc cells project to either the associative or sensorimotorregions of the striatum (Parent 1996, Blandini et al 2000).

1.3.1.5 Zona incertaThis collection of glutamatergic and GABAergic neurones, together with somedopaminergic ones as well, forms a distinct zone ventral to the thalamus (figure 1.2)and lateral to the hypothalamus. It has widespread connections across the neuroaxis,from the spinal cord to the cerebral cortex, with the heaviest of these involving theintralaminar and higher-order nuclei of the thalamus and various nuclei of thebrainstem, including the superior colliculus, pedunculopontine tegmental nucleus,SNr and the midbrain and pontine reticular formations (Mitrofanis 2005). The zonaincerta has been implicated in distinct functions, namely shifting attention, main-taining posture and locomotion, controlling visceral activity and generating arousal.

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It is the posture and the associated locomotion type function that link the zonaincerta with parkinsonian-like disorders (Mitrofanis 2005, Plaha et al 2006).

1.3.1.6 Pedunculopontine tegmental nucleusThis nucleus lies in the caudal parts of the midbrain and rostral regions of the pons,bordering the fibres of the medial meniscus and superior cerebellar peduncle(Pahapill and Lozano 2000). There are two distinct regions of the nucleus, thepars compacta, found within the caudal and dorsolateral part of the nucleus and thepars dissipata, found within the superior cerebellar peduncle and central tegmentaltract (Pahapill and Lozano 2000, French and Muthusamy 2018). Within theseregions there are also many cholinergic and glutamatergic neurones, as well as somedopaminergic, noradrenergic and GABAergic neurones (Pahapill and Lozano 2000,French and Muthusamy 2018). Major inputs to the pedunculopontine tegmentalnucleus arise from the globus pallidus, SNr, subthalamic nucleus, and the cervicaland lumbar areas of the spinal cord (Pahapill and Lozano 2000, French andMuthusamy 2018). The outputs of the pedunculopontine tegmental nucleus areextensive and include the thalamus, zona incerta, substantia nigra (SNc inparticular), subthalamic nucleus, globus pallidus, striatum, the midbrain, pontineand medullary reticular formations, deep cerebellar nuclei and the spinal cord(Pahapill and Lozano 2000, French and Muthusamy 2018). In terms of function inmotor control, the pedunculopontine tegmental nucleus forms part of a generalregion of the brainstem referred to as the midbrain locomotor region. Afterstimulation of the pedunculopontine tegmental nucleus, hypotonia and locomotionare generated (Takakusaki 2008, French and Muthusamy 2018). The pedunculo-pontine tegmental nucleus is thought to carry out these functions by activatingexcitatory medullary reticulospinal projections in the case for locomotion andinhibitory pontine reticulospinal projections in the case for hypotonia(Takakusaki 2008, French and Muthusamy 2018).

1.3.2 Overall functions of basal ganglia

Collectively, the basal ganglia family of nuclei have long been considered to beinvolved in motor function. They do not necessarily make a movement, but ratherthey - together with the overlying frontal regions of the cerebral cortex - help planand programme a movement for primary motor cortex and the spinal cord that havemore direct access to the somatic muscles (Monchi et al 2006). The basal ganglia arealso thought to help focus and filter particular movements, as well as starting andstopping stored automatic motor programmes such as walking, swimming, writing.In addition to these motor-related functions, more recent investigations haverevealed that the basal ganglia are involved in cognitive functions also, such aslearning and memory, presumably focusing and filtering these functions in a similarway as for the motor system (Parent 1996, Blandini et al 2000, Bergman andDeuschl 2002, Monchi et al 2006, Crittenden and Graybiel 2011, Kalia and Lang2015, Oertel 2017, Poewe et al 2017).

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1.3.3 The loops

Within the framework of the basic pattern of connectivity between the basal ganglianuclei described above, there exists a series of rather complex neural loops. Eachloop involves the cortex projecting to the striatum and subthalamic nucleus, thatthen project to the globus pallidus and SNr. These latter nuclei, after beinginfluenced by the subthalamic nucleus, then project to the thalamus, that thenrelays back to the cortex, thus completing the loop (purple arrow, figure 1.2). Thereare several of these cortical–basal ganglia–thalamic–cortical loops, namely thelimbic, prefrontal-associative, oculomotor and motor, each one associated withtheir functionally corresponding areas of the basal ganglia, thalamus and cortex.The SNc contributes to each loop, by projecting almost exclusively to the striatum,while the zona incerta and pedunculopontine tegmental nucleus receive inputs fromthe globus pallidus and SNr and have many of their projections directed towards thespinal cord (Parent 1996, Blandini et al 2000, Pahapill and Lozano 2000, Bergmanand Deuschl 2002, Nandi et al 2002a, 2002b, Mitrofanis 2005, Plaha et al 2006,French and Muthusamy 2018).

1.3.4 The direct and indirect pathways

Although many of the details of the inner workings of the cortical–basal ganglia–thalamic–cortical loops remain unknown, a functional model has been proposed(Albin et al 1989, Alexander et al 1990, Delong and Wichmann 2007, Obeso et al2008). The model relies on the notion of two distinct pathways within each loop—thedirect and indirect pathway—allowing for the flow of cortical information throughthe basal ganglia (figure 1.3). It should be noted that despite recent findings indicatingsome deficiencies in the model, it remains the single most complete paradigm fornormal and abnormal basal ganglia function (DeLong and Wichmann 2009).

In general, the direct pathway is associated with neuronal activation in thethalamus and cortex, whether for movement or cognition, while the indirectpathway is involved in neuronal suppression, in particular, in areas of the cortexand thalamus not activated by the direct pathway (figure 1.3: Albin et al 1989,Alexander et al 1990, Delong and Wichmann 2007, 2009, Obeso et al 2008). Thedirect pathway functions through the striatum and globus pallidus (and SNr) toactivate thalamic (ventral lateral, medial dorsal and intralaminar nuclei) and hencecortical (prefrontal, motor, somatosensory) activity, while the indirect pathwayworks through the striatum, globus pallidus (and SNr) and the subthalamic nucleusto suppress activity of the thalamus and cortex. The subthalamic nucleus is the keyplayer in the indirect pathway, in that it exerts a powerful excitatory effect on theglobus pallidus (and SNr) that then inhibits the thalamus and cortex. The activity ofthe subthalamic nucleus was thought to be controlled largely, if not exclusively, bythe inhibitory inputs from the globus pallidus (and SNr), but in more recent times,the cortex has also been considered a major drive of subthalamic activity. Thedopaminergic projections from the SNc to the striatum are involved in stimulatingthe direct pathway, while inhibiting the indirect pathway, with the overall resultbeing thalamic activation. The dopaminergic projections of the SNc, as with the

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subthalamic projections, are driven by the cortex (Albin et al 1989, Alexander et al1990, Delong and Wichmann 2007, 2009, Obeso et al 2008).

With the use of the direct and indirect pathways, activating and suppressingdifferent areas of the thalamus and cortex within each loop, the basal ganglia canhelp focus or filter particular functions for instance, certain movements in the motorloop or cognitive thought processes in the prefrontal-associative loop (Albin et al1989, Alexander et al 1990, Delong and Wichmann 2007, 2009, Obeso et al 2008).

Figure 1.3. Schematic diagram of a coronal section showing the so-called direct (green) and indirect (red)pathways of the basal ganglia, working within each cortical–basal ganglia–thalamic–cortical loop undernormal circumstances (depicted in figure 1.2). The circles along each pathway represent a neuronal relay orsynapse. The direct pathway results in neuronal activation while the indirect pathway in neuronal suppression—in this way the basal ganglia may focus or filter functions, whether they are movements or thoughts. Thedopaminergic inputs of the SNc (blue) influence the direct and indirect pathways at the level of the striatum;these inputs stimulate the direct pathway, while inhibiting the indirect, resulting in overall neuronal activation.The section is from the same region as depicted in the red box in figure 1.2(B). The SNr involvement (not shown)is similar to that of the globus pallidus. The association of the zona incerta and pedunculopontine tegmentalnucleus are not defined, but they may be also involved as part of the direct and direct and indirect pathway(dotted lines).

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The particular effects of the direct and indirect pathways on the zona incerta andthe pedunculopontine tegmental nucleus have not been well-defined (figure 1.3).They receive inhibitory inputs from the globus pallidus (and SNr), that in turn, aredriven by the subthalamic nucleus. Hence, the activity of the zona incerta andpedunculopontine tegmental nucleus, in particular their projections to the spinalcord, may be influenced considerably by subthalamic and pallidal activity, forexample, activating or suppressing locomotion and/or muscle tone (Pahapill andLozano 2000, Bergman and Deuschl 2002, Nandi et al 2002a, 2002b, Mitrofanis2005, Plaha et al 2006, French and Muthusamy 2018).

1.3.5 Summary

The basal ganglia family are a collection of highly interconnected nuclei foundacross the forebrain and brainstem. Through a series of complex and distinct circuitloops and pathways through the cortex, basal ganglia, thalamus and back to cortex,these basal ganglia nuclei are thought to be integral in focusing, filtering, stoppingand/or starting particular motor functions and cognitive thought processes.

1.4 Pathophysiology1.4.1 Zones of neuronal pathology

With such a striking and debilitating clinical syndrome, one would think thatParkinson’s disease patients would have a widespread and massive degeneration ofneurones across the brain. On the contrary, the zones of pathology, up until the latestages of the disease, are rather discrete, affecting only small groups of neurones. Forthe most part, these pathological zones lie deep in the brain, within the brainstem.

The main zone of pathology is within SNc (figures 1.4–1.6). The neurones of theSNc, most of which are dopaminergic (see action above on basal ganglia), undergo aprogressive degeneration over a period of many years (Rinne 1993, Parent 1996,Blandini et al 2000, Bergman and Deuschl 2002, Kalia and Lang 2015, Poewe et al2017). The loss of these neurones leads subsequently to a reduction in the levels ofdopamine in the striatum, the major synaptic hub of the basal ganglia, where thebulk of functional dopaminergic neurotransmission takes place (figure 1.5: Parent1996, Blandini et al 2000, Bergman and Deuschl 2002, Kalia and Lang 2015, Poeweet al 2017). The clinical signs of the disease start to become expressed after anywherebetween 60%–80% of the dopaminergic neurones and their striatal terminations arelost. It has been reported that there is a ∼5% loss of neurones in the SNc each decadeafter onset (Fearnley and Lees 1991, Cheng et al 2010).

In addition to this primary loss of dopaminergic neurones from SNc there are alsolosses in other localised regions, including the dopaminergic neurones of theadjoining ventral tegmental area and retrorubral field of the midbrain and thoseof the olfactory bulb, the noradrenergic neurones of the locus coeruleus, thecholinergic neurones of the pedunculopontine tegmental nucleus, the serotonergicneurones of the raphe nuclei, together with neurones of the dorsal motor nucleus ofthe vagus nerve (figure 1.6). At much later stages of the disease, there is also someloss of neurones across the cortex (Halliday et al 1990, Mavridis et al 1991, Braak

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et al 2003, Zarow et al 2003, Langston 2006, Del Tredici and Braak 2013,Brettschneider et al 2015, French and Muthusamy 2018).

It should be noted that there appears to be some key differences in the patterns ofdegeneration of the dopaminergic neurones within the SNc and surrounding regionsin the different clinical forms of the disease. In the tremor-dominant forms, there is agreater neuronal loss within the retrorubral field, while for the akinesia–bradyki-nesia-rigidity forms, the loss is greatest in the ventrolateral part of the SNc (Kaliaand Lang 2015, Magrinelli et al 2016, Poewe et al 2017).

1.4.2 Lewy bodies and α-synucleinThese pathological features, in particular within the main zone of pathology in theSNc, provide a key signature for diagnosis of Parkinson’s disease. The clinical

Figure 1.4. Schematic diagrams of coronal sections of the midbrain showing the distribution zones of thepigmented (dopaminergic) neurones in the SNc of a normal subject (A) and a Parkinson’s disease patient (B).The SNc forms the main zone of pathology in Parkinson’s disease.

Figure 1.5. Schematic diagrams summarising the major patterns of the distributions of dopaminergic (tyrosinehydroxylase+) neurones in the SNc and their terminals in the striatum in normal cases (A) and in Parkinson’sdisease (B). Please see figure 1.2 as to orientate these schematics of SNc and striatum within the greater brain.

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diagnosis is confirmed with a post-mortem analysis of a reduced number of neuronesin the SNc, together with the presence of abnormal aggregates of protein within thecytoplasm, called Lewy bodies (figure 1.7(B)), in the surviving SNc neurones.Further, that there is no evidence of other pathology across the brain that mayhave produced the signs and symptoms of Parkinson’s disease (Kalia and Lang2015, Poewe et al 2017).

The main protein that makes up the distinctive Lewy bodies, of which can befound in other disorders, such as Lewy body dementia, has been identified as α-synuclein. Under normal circumstances, the function of α-synuclein is not clear, butit has been found in the cytoplasm, mitochondria and nucleus of normal, otherwise‘healthy’ neurones and is thought to have a role in synaptic transmission andmitochondrial function. The factors that trigger the abnormal aggregation of this

Figure 1.6. Schematic diagram of a coronal section showing the main zones of pathology of the brain inParkinson’s disease. The grey shading in the nuclei indicates normal neuronal distribution, while the pinkshading indicates the zones of pathology and neuronal loss (right-hand side). The slightly darker pink shadingin the SNc indicates that it is the main zone of pathology. Note that the massive loss of dopaminergic neuronesin the SNc results in a substantial loss of their terminations within the striatum (not shown). In addition, atvery late stages of the disease, there is also some loss of neurones in the cortex (not shown).

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α-synuclein protein in disease are again not clear, but are likely to include theoccurrence of mutations that increase its production, together with the likelihood formisfolding leading to impaired pathways that cause its degradation. The build up ofα-synuclein in neurones is considered toxic, causing many intrinsic neuronalmalfunctions and ultimately degeneration. In the ageing system, neurones are lesslikely to have efficacious intrinsic mechanisms to prevent the accumulation of α-synuclein and its subsequent toxicity (Vekrellis et al 2011, Burré 2015, Kaushik andCuervo 2015, Soldner et al 2016).

The presence of α-synuclein appears key to the pathology of Parkinson’s diseaseand its spread across different neuronal populations. Indeed, it has been suggestedthat Parkinson’s disease is a prion disease, with the abnormal misfoldings andaggregates of α-synuclein within particular neurones being transported along theiraxons, only to be transferred to other neurones after release into extracellular space(Angot et al 2010, Brundin et al 2010). In fact, the expression of Lewy bodies andaggregates of α-synuclein have been reported to appear first, during the prodromalphase of the disease, in the olfactory bulb, the dorsal motor nucleus of vagus andenteric nervous system innervating the gastrointestinal system (figure 1.8). Takentogether, the expressions in these structures form the substrate for the initial non-motor, prodromal symptoms of the disease, namely anosmia and constipation(Braak et al 2004, Hawkes et al 2007, George et al 2013, Berg et al 2015, Mahlknechtet al 2015). The Lewy bodies and aggregates of α-synuclein then propagate to theSNc through synaptically linked connections and then further on to other regions ofthe brainstem (figure 1.8). For reasons that are not clear at present, the dopami-nergic neurones are especially vulnerable to propagated α-synuclein aggregates(Brundin and Melki 2017, Surmeier 2018). At this stage, with the involvement of theSNc, the distinct motor signs begin to develop. At later stages, the aggregates spreadto the cortex and define the end-points of the disease (Braak et al 2004, Hawkes et al2007).

Figure 1.7. (A) and (B) show schematic diagrams of dopaminergic neurones in normal (A) and in Parkinson’sdisease (B) cases. In Parkinson’s disease, neurones shows pathological changes in their dendrites, axons andsoma, together with the distinctive Lewy body (α-synuclein aggregates) in the cytoplasm.

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1.4.3 Gliosis

In contrast to these losses of particular types of neurones, Parkinson’s disease isassociated also with a marked gliosis, the hypertrophy and proliferation of the maintypes of glial cells, namely the astrocytes and microglia. In animal models of thedisease, many authors have reported that gliosis in the basal ganglia occurs almostimmediately after parkinsonian insult; thereafter, microglia tend to return tocontrol-like levels before the astrocytes, within a matter of weeks (McGeer andMcGeer 1998, 2008, Barcia et al 2003).

Figure 1.8. (A) Schematic diagrams showing the suspected spread of Lewy bodies and α-synuclein aggregatesacross the brain and body. The spread from the enteric nervous system of the gastrointestinal system and theolfactory bulbs, propagates along the vagus (X) nerve to the dorsal motor nucleus of the medulla, and thenthrough neuronal connections to the SNc and beyond. At very late stages, aggregates are also found in thecortex (not shown). The red box in the brain section of (B) indicates the approximate region of the brain areadepicted in (A).

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Classically, the hypertrophy and proliferation of astrocytes and microglia havebeen associated with a detrimental effect on neurones, by either inhibiting axonalregeneration by forming glial scars and/or secreting pro-inflammatory cytokines andother neurotoxic products. More recently, gliosis has also been associated with morebeneficial effects after lesion, for example, with the release of growth factors such asthe glial derived neurotrophic factor (GDNF). The relationship between a toxic andbeneficial function appears complex, being dependent on an array of differentfactors and molecular signalling mechanisms, and may change with time after theinjury (McGeer and McGeer 1998, 2008, Barcia et al 2003).

It is likely that the gliosis and inflammatory process is not the initial trigger for theonset of disease, but seems essential to the ongoing pathology. Indeed, there is acomplex relationship between gliosis and the inflammatory process and the develop-ment and propagation of α-synuclein misfolding, with one tending to aggravate orspur-on the other (Lema Tomé et al 2013, Ransohoff 2016, Poewe et al 2017). Thedetails of these relationships and mechanisms are far from clear at this stage,however.

1.4.4 Growth factors

Growth or trophic factors are a family of proteins, that include IGF (insulin-likegrowth factor), VEGF (vascular endothelial growth factor), FGF (fibroblast growthfactor), NGF (nerve growth factor), BDNF (brain derived neurotrophic factor) andGDNF, that are involved, not only in the normal function, maintenance andhomoeostasis of healthy neurones in the adult (e.g. increase in dopaminergictransmission) and the specification and maturation of neurones during early develop-ment, but also in the protection and repair of distressed or damaged neurones indisease and/or after injury (Siegel and Chauhan 2000, Ibáñez 2007). These proteinscan be picked up by neuronal terminals and transported retrogradely to the soma,where they then induce gene expressions within the nucleus to promote neuronalsurvival and phenotype specification (Ibáñez 2007, da Silva et al 2016, 2018).

In normal healthy brains, growth factor expression is generally found withinneurones, while in the diseased or injured brain, this expression shifts more towardsthe glial cells (Saavedra et al 2008). In fact, the strong expression of growth factorswithin the neurones in the diseased and/or injured state is considered a more acute,transient activity-dependent response, whereas growth factor expression in the glialcells is more reflective of a more chronic, delayed-persistent one (Hughes et al 1999).

In Parkinson’s disease, although there are reports of changes in the expression ofother growth factors, such as BDNF, FGF and NGF (Nakajima et al 2001, Yurekand Fletcher-Turner 2001, Nakagawa et al 2005, Chen et al 2006), GDNF is the keyprotein of this family in this disease, and has received the most scrutiny over theyears (Nakagawa and Schwartz 2004, Chen et al 2006). In animal models,particularly soon after the parkinsonian insult—that is, a few weeks—there is anacute endogenous increase in GDNF expression in the striatum (Nakajima et al2001, Yurek and Fletcher-Turner 2001, El Massri et al 2017). This increaseapparently reduces to baseline levels soon thereafter (Nakajima et al 2001, Yurek

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and Fletcher-Turner 2001) and is more evident in younger animals than in olderones (Yurek and Fletcher-Turner 2001, Collier et al 2005). The GDNF increase hasbeen associated with a repair and regrowth of dopaminergic axons and terminations,but this is far from clear at present (Saavedra et al 2008). In Parkinson’s diseasepatients however, most studies report a reduction in endogenous levels of GDNF inboth the SNc (Chauhan et al 2001) and striatum (Backman et al 2006), and it hasbeen suggested that these reductions contribute to the degeneration of the dopami-nergic neurones (Siegel and Chauhan 2000, Mattson and Magnus 2006, Saavedraet al 2008). There have been several pharmaceutical approaches tested in the hope ofstimulating endogenous GDNF with some promising early findings (d’Anglemontde Tassigny et al 2015, Baranov et al 2017).

Although developments associated with stimulating endogenous GDNF areencouraging, most previous and ongoing studies have explored the effects ofexogenously applied GDNF in Parkinson’s disease (McBride and Kordower 2002,Kordower and Bjorklund 2013, d’Anglemont de Tassigny et al 2015, Kalia andLang 2015, Poewe et al 2017, Torres et al 2017). Such applications have, forexample, been with direct injection of GDNF or GDNF-loaded microspheres,transplants of GDNF producing cells, systemic administration of GDNF-nano-liposomes engineered to cross the blood–brain barrier, or using gene transfer withviral vectors (d’Anglemont de Tassigny et al 2015). These have, on the whole,resulted in positive outcomes in animal models of the disease, with improvements inbehaviour and neuroprotection being evident in each case (McBride and Kordower2002, Kordower and Bjorklund 2013, d’Anglemont de Tassigny et al 2015, Kaliaand Lang 2015, Poewe et al 2017, Torres et al 2017). Despite these successes inanimal models, translation of GDNF therapy to patients has encountered problems,including the method of sustained delivery and surgical complications, but there areongoing plans for improvements (McBride and Kordower 2002, Kordower andBjorklund 2013, d’Anglemont de Tassigny et al 2015, Kalia and Lang 2015, Oertel2017, Poewe et al 2017, Torres et al 2017, Whone et al 2019).

1.4.5 Other pathological changes

Some of the structural and functional changes in the striatum (the main synapticinterface of the basal ganglia) in Parkinson’s disease are worthy of further comment.The most distinctive features of the striatum after parkinsonian insult include themassive reduction in dopaminergic terminations, together with a marked increase inglial activity (see sections above on zones of pathology and gliosis). There are alsoother more subtle structural and functional changes, notably some dendriticremodelling by the spiny projection neurones (Sterling et al 2013), as well as anincrease in the activity of the giant cholinergic interneurones (Lim et al 2014).

In addition, there are some curious changes evident among a resident populationof putative dopaminergic, tyrosine hydroxylase containing, interneurones of thestriatum (Dubach et al 1987, Tashiro et al 1989, Betarbet et al 1997). These neuronesundergo a striking increase in number after parkinsonian insult, an increaseconsidered a compensatory response to the massive loss of dopamine terminations

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in the striatum (Betarbet et al 1997, Meredith et al 1999, Porritt et al 2000, Palfi et al2002, Cossette et al 2005, Mazloom and Smith 2006, Tandé et al 2006, Sebastiánet al 2007, Ünal et al 2013, Depboylu 2014, Xenias et al 2015). While there is somedebate as to whether these neurones actually produce dopamine, with distinctdifferences being reported between rodents and primates in the expressions of keyenzymes involved in dopamine production (Betarbet et al 1997, Meredith et al 1999,Porritt et al 2000, Palfi et al 2002, Cossette et al 2005, Tandé et al 2006, Weihe et al2006, Depboylu 2014, Xenias et al 2015), these neurones have been reported toincrease even further in number when the growth factor, GDNF, is introduced to thestriatum in animal models of Parkinson’s disease (Palfi et al 2002, Sebastián et al,2007). Further, the parkinsonian animals treated with GDNF, and have an increasein the number of tyrosine hydroxylase+ striatal neurones, show a reduction inclinical scores and an improvement in motor behaviour (Sebastián et al 2007).

1.4.6 Mechanisms of neuronal death

The mechanisms underpinning the degeneration of neurones in Parkinson’s disease,regardless of the initial trigger (e.g. environmental toxin or genetic mutation), havecome under much scrutiny in recent years. The majority of the focus has been on thedopaminergic neurones and their mechanisms of death. There is general agreementthat these mechanisms are apoptotic, a slow breakdown of cellular constituents (e.g.after exposure to low levels of toxicity), rather than necrotic, a more rapidbreakdown of cellular constituents (e.g. after exposure to high levels of toxicity;Tatton and Olanow 1999). This apoptotic process appears to involve two, notnecessarily mutually exclusive, mechanisms, namely mitochondrial dysfunction andLewy body accumulation (Surmeier 2018).

It has been clear for a number of years that mitochondrial dysfunction plays a keyrole in the process of degeneration (Dauer and Przedborski 2003, Schapira 2011,Exner et al 2012, Haelterman et al 2014, Schapira et al 2014). Mitochondria are theengine rooms of neurones; they produce the energy (adenosine triphosphate; ATP)that fuels so many intrinsic cellular pathways and generate factors that reduce theoxidative stress of neurones. After parkinsonian insult, there is a progressiveaccumulation of mutations in mitochondrial DNA that reduce efficient mitochon-drial function. This process leads to an increase in the levels of reactive oxygenspecies, generating oxidative stress. This toxicity leads subsequently to neuronaldeath (figure 1.9: Schapira 2011, Exner et al 2012, Haelterman et al 2014, Schapiraet al 2014). Some of the key evidence for mitochondrial dysfunction in Parkinson’sdisease comes from evidence that many experimental toxins used in animal models,such as 6OHDA (6 hydroxydopamine) or MPTP (methyl-4-phenyl-1,2,3,6-tetrahy-dropyridine), target the mitochondria and cause extensive oxidative stress anddamage, leading to neuronal death (Schober 2004, Tieu 2011, Blandini andArmentero 2012, Blesa et al 2012, Bové and Perier 2012; see below). Further,many of the gene mutations associated with the disease, for example in DJ-1 (PARK7), PINK1 (PARK 6), parkin (PARK 2), SNCA (PARK 1) and LRRK2 (PARK 8)have been linked to mitochondrial dysfunction and subsequent neuronal death

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(Bonifati 2007, 2012, Corti and Brice 2013, Cannon and Greenamyre 2013, Beilinaand Cookson 2016). Finally, low levels of mitochondrial complex I (the largestenzyme complex in the electron transport chain driving ATP production) have beenreported in Parkinson’s disease patients (Schapira et al 1989).

The reasons why dopaminergic neurones are particularly susceptible to mito-chondrial dysfunction and oxidative stress are not clear, but several lines of evidenceindicate that it is due to their exceptionally high energy requirement. These neuroneshave an autonomous pacemaking activity that involves cytosolic calcium oscilla-tions and calcium extrusion (Surmeier et al 2017); further, they have many synapsesacross axons that extend for long distances, some up to four and a half metres(Bolam and Pissadaki 2012). These factors require a considerable amount of energyto maintain, one that is provided by their mitochondria and, if these are dysfunc-tional, the neurones suffer severe consequences, namely oxidative stress and death(Poewe et al 2017, Surmeier 2018).

A second putative theory behind the degeneration of the dopaminergic neuronesfocuses on their accumulation of Lewy bodies (figure 1.7, 1.9). The Lewy bodies are

Figure 1.9. Schematic diagrams of mitochondrial dysfunction in Parkinson’s disease. The damaged mitochon-dria results ultimately in the death of the neurones. Note that α-synuclein aggregates may occur in the nucleus,cytoplasm, as well as the mitochondria. The small red circle in the diseased neurone indicates a region ofmagnification, one of the regions where there would be dysfunctional mitochondria.

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made up mainly by aggregations of α-synuclein, that are considered toxic to theneurones (Vekrellis et al 2011, Burré 2015, Kaushik and Cuervo 2015, Soldner et al2016). Under normal circumstances, there appears to be low levels of α-synucleinwithin the mitochondria, but when factors unknown stimulate an increase inaccumulation, this leads to mitochondrial complex I deficits, oxidative stress andneuronal death (figure 1.9: Devi et al 2008, Nakamura 2013). Indeed, the first genemutation that was discovered associated with Parkinson’s disease was, in fact, theSNCA gene, one that encodes α-synuclein (Polymeropoulos et al 1997). Thesefactors all point to the Lewy bodies, the α-synuclein aggregations, being a key factorin the death of the dopaminergic neurones (Kalia and Lang 2015, Poewe et al 2017,Surmeier 2018).

In addition to these two central mechanisms generating the death of dopaminer-gic neurones, there are several others that may contribute. Further exacerbating theneurodegeneration are glutamate excitotoxicity (Albin and Greenamyre 1992,Blandini et al 1996, 2010, Piallat et al 1996, Wallace et al 2007), an inflammatoryprocess (McGeer andMcGeer 1998, 2008, Barcia et al 2003) and an accumulation ofvarious metals (Ward et al 2014, Hare and Double 2016, Aaseth et al 2018). Theglutamatergic inputs to the dopaminergic neurones, particularly those from thesubthalamic nucleus and perhaps the pedunculopontine tegmental nucleus also(Parent 1996, Blandini et al 2000, Pahapill and Lozano 2000, Bergman and Deuschl2002, Nandi et al 2002a, 2002b, Plaha et al 2006, French and Muthusamy 2018),become overactive in Parkinson’s disease and the excessive glutamate promotesmitochondrial defects within the dopaminergic neurones. With regard to theinflammatory process, glial cells, both microglia and astrocytes, under normalconditions, support neuronal function; in the adverse parkinsonian condition,however, they may become reactive and toxic to neurones, generating a sustainedlocal inflammation within the basal ganglia, in particular the SNc and the striatum(McGeer and McGeer 1998, 2008, Barcia et al 2003). Finally, there is evidence thataccumulation of iron and copper in dopaminergic neurones of the SNc is toxic,generating oxidative stress, and contributes to the progression of Parkinson’s disease(Ward et al 2014, Hare and Double 2016, Aaseth et al 2018).

1.4.7 Neural circuits behind the signs and symptoms

The neural circuits that underpin the motor signs and non-motor symptoms ofParkinson’s disease have been under investigation for many years. Although thebulk of the details are still unclear, some key features are evident for most of thesigns and symptoms.

For the motor signs, and presumably for the cognitive deficits also, the primaryloss of midbrain dopaminergic cells in Parkinson’s disease produces a cascade ofabnormal circuitry within the basal ganglia. In particular, the reduced dopaminelevels in the striatum seem to affect the activity of the indirect pathway the most(figure 1.10). The dopaminergic inhibition of this pathway is lost, and as aconsequence, the subthalamic nucleus becomes overactive and stimulates the globuspallidus (and SNr) to over-inhibit the thalamus and cortex, leading to less motor

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and/or cognitive activity (Albin et al 1989, Alexander et al 1990, Parent 1996,Blandini et al 2000, Pahapill and Lozano 2000, Bergman and Deuschl 2002, Delongand Wichmann 2007, 2009, Obeso et al 2008). As for pedunculopontine tegmentalnucleus and zona incerta, these nuclei are inhibited also, particularly their descend-ing pathways to the spinal cord, and this may also contribute to reduced motoractivity (figure 1.10: Pahapill and Lozano 2000, Nandi et al 2002a, 2002b,Mitrofanis 2005, Plaha et al 2006, French and Muthusamy 2018). It has becomeclear over the last few years that central to all these abnormal networks is the

Figure 1.10. Schematic diagram of a coronal section showing the abnormal pathways in Parkinson’s disease.After loss of dopamine from the striatum, the indirect pathway becomes overactive (there is also someunderactivity of the direct pathway, but this is not as prominent and is not shown). This leads to overactivity ofthe globus pallidus and subthalamic nucleus leading to over-inhibition of the thalamus and cortex. Thispathway also presumably over-inhibits the pedunculopontine tegmental nucleus and the zona incerta. Themotor signs of the disease appear to involve different circuits. The tremor circuit appears to relate to the over-inhibition of the thalamus while the akinesia–bradykinesia-rigidity circuit relates to the pedunculopontinetegmental nucleus, and perhaps also the zona incerta, and their projections to the spinal cord. For bothcircuits, the subthalamic overactivity is the major drive, resulting after a loss of dopamine from the striatum.The SNr involvement (not shown) is similar to that of the globus pallidus. The cerebellar involvement in thetremor circuit is not shown. The section is from the same region as depicted in the red box in figure 1.2(B).

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subthalamic nucleus (Kalia and Lang 2015, Poewe et al 2017). As a consequence, thebulk of the therapeutics for the disease, for example, surgical intervention, havetargeted the subthalamic nucleus (Ashkan et al 2004, Benabid et al 2009).

There is evidence that the two main sets of motor signs of the disease, namelyresting tremor and akinesia–bradykinesia-rigidity, involve different neural circuits.Abnormality in both circuits begins with dopamine depletion in the striatum andsubsequent overactivity in the subthalamic nucleus, but thereafter, the circuitsappear to involve different centres (figure 1.10). This notion has stemmed fromseveral, predominantly clinical, observations. For instance, tremor does not progressat the same rate, nor correlate well, with the signs of akinesia, bradykinesia andrigidity. Further, tremor may occur on the side contralateral to the side of mostakinesia, bradykinesia and rigidity and generally responds less well and moreinconsistently to dopamine replacement drug therapy (Helmich et al 2012).

The tremor circuit involves the thalamus as a centre-piece (figure 1.10). Theoveractivity of the subthalamic nucleus triggers excessive inhibitory pallidal outputto the thalamus, generating altered firing patterns and rhythmic bursting activity ofthalamic neurones, that then generates abnormal activity in the motor cortex(Bergman and Deuschl 2002, Brodkey et al 2004, Dovzhenok and Rubchinsky2012, Helmich et al 2012, Duval et al 2016, Dirkx et al 2016, 2017). The tremoroscillations are localised within the basal ganglia–thalamo–cortical circuit andtremor-related activity has been recorded within each component of this circuit,namely within the subthalamic nucleus, globus pallidus, thalamus and cortex. Thisabnormal circuitry only emerges at stasis/rest when the basal ganglia are notinvolved in voluntary movement. Surgical treatment, breaking the loop, at anyone of these neural sites leads to the same effect, suppression of the tremor. Thecerebellum also appears to be involved, possibly through its terminations in thethalamus and intrinsic thalamic connections via, say, the thalamic reticular nucleus.It has been suggested that tremulous activity starts in the basal ganglia and then ispropagated along the cerebello–thalamo–cortical loop, that the basal gangliatriggers the tremor (like a light switch), while the cerebello–thalamo–cortical loopdetermines tremor amplitude (like a light dimmer). Taken all together, and althoughmany of the details are far from clear, the tremor of Parkinson’s disease appears tobe induced by abnormal basal ganglia activity, relayed by the thalamus to the cortexand influenced by the cerebellum (Bergman and Deuschl 2002, Brodkey et al 2004,Dovzhenok and Rubchinsky 2012, Helmich et al 2012, Duval et al 2016, Dirkx et al2016, 2017).

It has long been thought that the akinesia–bradykinesia-rigidity circuit alsoinvolved the thalamocortical loop, that these signs manifest after inhibition of thethalamus, and hence cortex, via the globus pallidus driven by an overactivesubthalamic nucleus (Albin et al 1989, DeLong and Wichmann 2007, Jankovic2008). However, there are indications that another, perhaps alternate, circuit isinvolved. This circuit does not involve the thalamus, but rather the locomotor andmuscle tone region of the brainstem, principally the pedunculopontine tegmentalnucleus, and presumably also the zona incerta (figure 1.10: Nandi et al 2002a, 2002b,Mitrofanis 2005, Plaha et al 2006, Takakusaki 2008, French and Muthusamy 2018).

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The overactive subthalamic nucleus in Parkinson’s disease may drive the inhibitoryprojections from the globus pallidus (and SNr) not only to the thalamus, but also tothe pedunculopontine tegmental nucleus and zona incerta. These two nuclei havedescending projections to the spinal cord and a major impact on locomotivemovement and muscle tone (Pahapill and Lozano 2000, Nandi et al 2002a,2002b, Mitrofanis 2005, Takakusaki 2008, French and Muthusamy 2018). Thisinhibition of the outflow of the pedunculopontine tegmental nucleus and zonaincerta could result in the signs of akinesia, bradykinesia and rigidity. There areseveral factors that lend strong support for this distinct neural circuit, particularlyregarding the involvement of the pedunculopontine tegmental nucleus; namely, thatthalamic surgery in Parkinson’s disease patients improves tremor, but not akinesia,bradykinesia and rigidity substantially, suggesting a circuit for the latter signs thatdoes not involve the thalamus (Benabid et al 2009); that the pedunculopontinetegmental nucleus in Parkinson’s disease patients shows substantial degeneration,which together with the presumed increase in inhibition to this nucleus, contributesto the signs of akinesia, bradykinesia and rigidity (Pahapill and Lozano 2000, Nandiet al 2002a, 2002b, French and Muthusamy 2018); and finally, that experimentallesions to the pedunculopontine tegmental nucleus in monkeys generate the signs ofakinesia, bradykinesia and rigidity but not tremor (Nandi et al 2002a, 2002b).

With regard to the non-motor symptoms of the disease, neural substrates havebeen reported and/or proposed for many of them; anosmia is linked to the presenceof Lewy bodies and neuronal loss in the olfactory nuclei, bulbs and tracts;constipation appears to involve the dysfunction and presence of α-synucleinaggregates within the enteric nervous system, together with the dorsal motor nucleusof the vagus; rapid-eye movement sleep behaviour disorders have been related to theloss of neurones in the pedunculopontine tegmental nucleus, locus coeruleus andraphe nuclei of the brainstem; depression is associated with the neuronal loss in thelocus coeruleus and raphe nuclei; while cognitive impairment is linked to neuronalloss and α-synuclein aggregates across the cortex. Dysphagia and dysarthria,although motor signs, are associated with the dysfunction of the dorsal motornucleus of the vagus nerve, that innervates the muscles of the pharynx and larynx(Braak et al 2004, Hawkes et al 2007, George et al 2013, Berg et al 2015, Mahlknechtet al 2015).

1.4.8 Predictive tests

Over the years, attempts have been made to develop an early indicator or biomarkerof Parkinson’s disease, particularly during the premotor or prodromal phase of thedisease. Unfortunately, as it stands, there is no accepted and/or reliable predictiveindicator for the disease.

Such a biomarker and predictive indicator would aid substantially in the earlytreatment of the disease, especially in relation to improving the effectiveness of adisease-modifying or neuroprotective therapy (Kalia and Lang 2015, Poewe et al2017). In this vein, many authors have used positron emission tomography or singlephoton emission computed tomography methods to examine any changes in

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dopamine levels and/or microglial activation within the basal ganglia and the earlyindications are most encouraging. Indeed, the development of extremely highresolution images—to obtain a clear view of individual neurones, similar that seenin histological sections—would be of enormous benefit to the cause (Brooks andPavese 2011, Kalia and Lang 2015, Poewe et al 2017).

In addition to these imaging methods, there are also investigations into determin-ing the extent of α-synuclein expression within the gastrointestinal system, namelywithin the enteric nervous system (Visanji et al 2014). These results are somewhatmixed. On the one hand, there have been some encouraging findings indicating α-synuclein being present within the intestines prior to onset of disease (Böttner et al2012, Kim et al 2017) and that vagotomy reduces the risk of Parkinson’s disease inpatients (Liu et al 2017) and parkinsonian pathology in animal models (Pan-Montojo et al 2012), while other findings indicate rich α-synuclein in controls(Visanji et al 2015) and limited spread of the protein from peripheral to centralnervous systems in animal models (Manfredsson et al 2018).

1.5 Risk factorsAlthough the precise causes of Parkinson’s disease, namely the factors that generatethe distinct patterns of pathophysiology are unclear, there are a number of riskfactors associated with the disease (Bonifati 2012, Poewe et al 2017).

1.5.1 Age

Age is a clear risk factor, with most cases being diagnosed in persons older than 50years. The structural and functional changes that occur in neurones in ageing, theintrinsic accumulation of aberrant proteins and free radicals, genetic mutations and/or mitochondrial defects, make them more susceptible to dysfunction and degener-ation (López-Otín et al 2013).

1.5.2 Environmental toxin

In this aged and more fragile state of the neurones, several factors may contribute tothe development of the disease. There are signs that an environmental toxin maytrigger onset of disease. Although the precise details are far from clear, repeatedexposure to pesticides, solvents, metals, and/or other pollutants can increase the riskof Parkinson’s disease (Cannon and Greenamyre 2013, Goldman 2014). Indeed,many of the animal models of the disease are based on exposure to variousneurotoxins, for example, paraquat, rotenone, 6OHDA or MPTP (Schober 2004,Blandini and Armentero 2012, Blesa et al 2012, Bové and Perier 2012). Themechanism of action of the toxins, for the most part, has been shown to causemitochondrial dysfunction, leading on to neuronal death (Schober 2004, Blandiniand Armentero 2012, Blesa et al 2012, Bové and Perier 2012).

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1.5.3 Vascular

There are also suggestions that Parkinson’s disease is a vascular disorder. Theneurones are thought to undergo cell death after endothelial cell damage andimpairment of the blood–brain barrier function (Farkas et al 2000, Kortekaas et al2005, Carvey et al 2009, Grammas et al 2011, Guan et al 2013). The degenerativevascular morphology seen in Parkinson’s disease includes the formation of endo-thelial cell clusters, that are presumed to contribute to the fragmentation ofcapillaries and a breakdown to the entire capillary network nourishing the neurones(Guan et al 2013). In this context, the toxins that induce parkinsonism in animalmodels, namely 6OHDA and MPTP (Schober 2004, Blandini and Armentero 2012,Blesa et al 2012, Bové and Perier 2012), have been shown to generate substantialdisruption of the blood–brain barrier, suggesting that at least part of their toxiceffect on neurones is through compromising the efficacy of the vascular system(Carvey et al 2009).

1.5.4 Head injury

Another factor that has been suggested to lead to Parkinson’s disease is head injury.This has been on the basis that such injuries lead to brain inflammation andbreakdown of the blood–brain barrier (Schmidt et al 2005), mitochondrial dysfunc-tion (Liu et al 2002), together with an increase in accumulation of α-synuclein (Uryuet al 2003). However, from a large number of epidemiological studies exploring therelationship between different forms of head injury and Parkinson’s disease, itappears no clear association is evident; at best, there is a borderline level ofsignificance (Pearce et al 2015).

1.5.5 Gender and race

It has also been known for many years that men are at greater risk of contractingParkinson’s disease than women, in fact one and a half times greater. The precisereasons for this gender difference are not clear, but several factors have beensuggested, for example, that oestrogen can be neuroprotective and that men, due tothe nature of many of their jobs, are more likely to be exposed to toxins and sufferhead trauma (Wooten et al 2004, Miller and Cronin-Golomb 2010).

There is also evidence for some disparity in the prevalence of Parkinson’s diseaseamong different races. In particular, many studies have reported that African–Americans are half as likely to be diagnosed with the disease as caucasians, and thishas been suggested to be based on biological, rather than socioeconomic factors. Aswith the gender differences, the reasons behind this racial difference are far fromclear (Dahodwala et al 2009, Poewe et al 2017).

1.5.6 Genetics

Contrary to the traditional view that Parkinson’s disease is the quintessentialidiopathic (of no known cause) neurological disease, a genetic component hasindeed been uncovered in more recent times. There is the evidence of an increased

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risk if there is a family history, together with the findings of complete concordance inmonozygotic twins of the disease, at least in the early-onset forms (<50 years of age;Tanner et al 1999).

Since the mid-1990s, after the discovery of the SNCA gene that encodes α-synuclein (Polymeropoulos et al 1997), mutations have been described in a numberof other genes. These include DJ-1 (PARK 7), PINK1 (PARK 6), parkin (PARK 2),and LRRK2 (PARK 8), many of which are associated with mitochondrialdysfunction (Bonifati 2007, 2012, Corti and Brice 2013, Cannon and Greenamyre2013, Beilina and Cookson 2016). The majority of these mutations have beenassociated with early-onset forms of the disease, less so with the late-onset ones andare prominent in only a small number of cases (10–15%). The current state ofopinion among most authors is that Parkinson’s disease, like many other neuro-logical disorders, results from a complex interaction between both genetic andenvironmental factors.

One should note that there are some interesting differences emerging between thegenetic and idiopathic forms of the disease, namely that the patterns of degenerationacross the brain are quite distinct. In the genetic forms, particularly the PINK1 andparkin forms, degeneration is rather localised to the dopaminergic neurones of theSNc (Poulopoulos et al 2012). This is very different to the more usual patterns of lossin the idiopathic form, that include a loss of neurones from other regions and can beassociated with other neurotransmitter systems as well (Halliday et al 1990, Zarowet al 2003, Langston 2006, Del Tredici and Braak 2013, Brettschneider et al 2015).There are also indications that the rates of clinical progression are very different inthe two forms of the disease. In the genetic forms, disease progression is slower andthere is a more sustained response to dopamine replacement drug therapy comparedto the idiopathic form (Bonifati 2012).

1.5.7 Summary

Taken all together, these factors—either genetic mutation, toxic insult, vasculardamage, head injury, gender, race, or other, as yet unknown factors—all target asimilar form of neuronal disruption and damage, namely Lewy body formation andmitochondrial dysfunction, leading to a reduction of key cellular functions andsubsequent neuronal death. This is a central feature in the pathogenesis ofParkinson’s disease.

1.6 Animal modelsA fundamental step in the further understanding of the process and mechanisms ofany given disease, together with the development of therapeutics, is the establish-ment of a range of animal models (e.g. McGonigle and Ruggeri 2014). In relation toParkinson’s disease, there have been a number of animal models that have beendeveloped and used over the years. It could be argued that of the five majorneurological afflictions, namely Parkinson’s disease, Alzheimer’s disease, schizo-phrenia, depression and multiple sclerosis, Parkinson’s disease has the most diverseand widely developed of animal models. In very broad terms, these models are

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categorised into either toxin-induced or transgenic (Schober 2004, Chesselet 2008,Tieu 2011, Blandini and Armentero 2012, Blesa et al 2012, Bové and Perier 2012).

1.6.1 Toxin-induced models

A key reason for Parkinson’s disease having the most extensive range of animalmodels rests on the fact that a number of toxins have been shown to induce manyfeatures of the disease. Most notably, MPTP, which was discovered accidentally inthe 1980s by a chemist attempting to produce the synthetic heroin, meperidine, forrecreational use (Langston et al 1983). After MPTP contamination, individualsdeveloped distinct parkinsonian signs, resting tremor and bradykinesia, and weretreated successfully, at least initially, with dopamine replacement drug therapy.Since that time, the environmental toxin theory of Parkinson’s disease has beenexpanded substantially and MPTP has developed into the most widely used animalmodel for the disease (Schober 2004, Tieu 2011, Blandini and Armentero 2012,Blesa et al 2012, Bové and Perier 2012). Indeed, results from the MPTP animalmodel over the years have generated much insight into the pathogenesis andmechanisms of the disease, together with offering a more than useful testing groundfor potential therapeutic treatments, particularly neuroprotective ones (Schober 2004,Tieu 2011, Blandini and Armentero 2012, Blesa et al 2012, Bové and Perier 2012).

The basic mechanism of MPTP toxicity involves MPTP crossing the blood–brainbarrier—after injection into the vascular system—where it is metabolised bymonoamine oxidase B in astrocytes and converted into the active toxin 1-methyl-4-phenylpyridinium (MPP+; Schober 2004, Tieu 2011, Blandini and Armentero2012, Blesa et al 2012, Bové and Perier 2012). MPP+ is then released into theextracellular space and absorbed by the neighbouring dopaminergic neurones, viathe dopamine transporter molecule. MPP+ accumulates within these neurones andcauses toxicity by an inhibition of multi-subunit enzyme complex 1 (NADH-ubiquinone oxireductase) and leads to oxidative stress and the death of thedopaminergic neurones (Schober 2004, Tieu 2011, Blandini and Armentero 2012,Blesa et al 2012, Bové and Perier 2012). The animals most used for the MPTP modelinclude mice and monkeys. For reasons that are not entirely clear, rats do notrespond well to MPTP toxicity and hence have very rarely been used with this model(Schober 2004, Tieu 2011, Blandini and Armentero 2012, Blesa et al 2012, Bové andPerier 2012).

It should be noted that, although there are many similarities in the patterns ofpathology and clinical signs between MPTP-treated animal models and idiopathicParkinson’s disease in humans, there are some differences. First, unlike inParkinson’s disease patients, the development of Lewy bodies and α-synucleinexpression in the brains of MPTP-treated animals is not commonplace (Schober2004, Tieu 2011, Blandini and Armentero 2012, Blesa et al 2012, Bové and Perier2012, Porras et al 2012). Second, although MPTP-treated models show most of themajor signs of the disease, including akinesia, bradykinesia, postural instability, andrigidity, resting tremor is seen rarely (Porras et al 2012). Third, the MPTP-treatedanimal models do not (for the most part) reflect the progressive nature of the disease,

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the impact in toxicity being more sudden. However, there are many chronic orsubacute versions of the MPTP-treated model available that tend to offset this issue.Fourth, the MPTP-treated model does not generate lesions across all the nuclei andneurotransmitter systems evident in idiopathic Parkinson’s disease patients.Notwithstanding these differences between the MPTP-treated animal models andpatients, one should not forget or dismiss that their similarities are, in fact, greater.Hence, the MPTP-treated model remains the most widely used model amongresearchers and has provided so many insights into the pathophysiology andpatterns of behavioural and clinical deficit in Parkinson’s disease (Schober 2004,Tieu 2011, Blandini and Armentero 2012, Blesa et al 2012, Bové and Perier 2012,Porras et al 2012).

The 6OHDA, hemi-parkinsonian model is another well-known toxin-inducedanimal model of Parkinson’s disease. This model has been used mainly in rats, thespecies that does not respond well to MPTP toxicity (see above), but also in mice.6OHDA enters the dopaminergic neurones by means of binding to the dopaminetransporter molecule and generates mitochondrial dysfunction and oxidative stress,leading to dopaminergic neuronal death (Schober 2004, Tieu 2011, Blandini andArmentero 2012, Blesa et al 2012, Bové and Perier 2012). Unlike MPTP, 6OHDAdoes not cross the blood–brain barrier and hence has to be injected directly into thebrain, usually within the SNc, medial forebrain bundle, or striatum. As a generalrule, injections into the SNc or medial forebrain bundle lead to much greaterpatterns of neuronal death in the SNc than after injections into the striatum. Thestandard behavioural test for 6OHDA lesion is the analysis of apomorphine-inducedrotations, as a measure of the extent of the nigrostriatal lesion (the more rotationsthe animal has after apomorphine injection, then the greater the lesion). As with theMPTP-treated model, although 6OHDA generates a lesion to the dopaminergicsystem and has yielded much useful data, it does have the limitation of being rathersudden impact and is not fully representative of the progressive nature of the disease(Schober 2004, Tieu 2011, Blesa et al 2012, Bové and Perier 2012).

Two other toxin-induced models of Parkinson’s disease, although not as widelyused as MPTP and 6OHDA, include the paraquat and rotenone models. Both ofthese cross the blood–barrier and enter dopaminergic neurones, causing mitochon-drial dysfunction leading to degeneration. They have also been reported to generateα-synuclein expression and Lewy body formation within neurones, together withassociated locomotive behavioural impairments in animals, mainly rodents. Theyboth suffer, however, in being either inconsistent in generating patterns ofpathology and behaviour, and/or having a substantially high mortality rate inanimals (Schober 2004, Tieu 2011, Blandini and Armentero 2012, Blesa et al 2012,Bové and Perier 2012).

1.6.2 Transgenic models

In addition to these major toxin-induced models, there are also several transgenicanimal models, from drosophila (flies) to mice (Chesselet 2008, Blandini andArmentero 2012, Blesa et al 2012). Transgenesis involves the transfer of foreign

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genetic material to induce specific alterations of gene expression. The most notablegenetic models that have been characterised for Parkinson’s disease, include the α-synuclein, leucine rich repeat kinase 2 (LRRK2), parkin, DJ-1, PINK1 and tauK3691 models. For the α-synuclein model, two mutations in the α-synuclein gene(A53T, A30P) have been used to create transgenic mice. These models generatemotor and non-motor deficits, together with Lewy body-type formations in neuro-nes. They do not, however, generate a major degeneration of the dopaminergicsystem, at least not in mice, but apparently in drosophila. Similar patterns ofpathology are, on the whole, evident in the other transgenic forms (Chesselet 2008,Blandini and Armentero 2012, Blesa et al 2012), although the tau K3691 mice doshow substantial dopaminergic neuronal degeneration (Ittner et al 2008). It shouldbe noted that when viral vectors inducing α-synuclein overexpression are injectedstereotaxically in the proximity of the SNc in rats, then a substantial loss—albeitlimited to the local region of injection—of dopaminergic neurones is evident(Chesselet 2008, Blandini and Armentero 2012). Taken all together, although thetransgenic models offer many features of Parkinson’s disease in patients, they do not(as with the toxin-induced models) offer the complete constellation.

1.6.3 Summary

There are a range of animal models of Parkinson’s disease that have been developedin drosophila, rodents and monkeys, from toxin-induced to transgenic, each showingmany of the features that characterise the human forms of the disease. In particular,there is a major degeneration in the SNc and denervation of the striatum, togetherwith many motor signs, from akinesia to rigidity. However, no single animal modeldisplays all the features of the disease. Nevertheless, a worthwhile picture of thedisease process and impact of any given therapeutic treatment can be gained fromgathering information from a range of models, from both toxin-induced andtransgenic, across a number of species, from drosophila to monkeys.

1.7 Current treatmentsOn diagnosis, with the onset of the first motor signs of the disease, patients aretreated with dopamine replacement drug therapy, that aims to replace the dopaminelost from the system. This is often the first-line therapy, being highly efficacious atreducing motor signs, at least initially. With prolonged use, however, the efficacy ofthe therapy tapers and side effects such as including motor response oscillations anddrug-induced dyskinesias develop (Bergman and Deuschl 2002, Jankovic 2008,Kalia and Lang 2015, Oertel 2017, Poewe et al 2017). At these stages, or when thedisease has progressed sufficiently, patients are usually recommended for surgerywith deep brain stimulation at high frequency, most commonly targeting thesubthalamic nucleus (Benabid et al 2009). This surgery serves to correct and/oradjust the abnormal activity of the basal ganglia generated by the loss of dopaminefrom the system (Ashkan et al 2004, Benabid et al 2009). As with the dopaminereplacement drug therapy, deep brain stimulation has been shown to be veryeffective in treating the motor signs of the disease (Benabid et al 2009).

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1.7.1 Dopamine replacement drug therapy

The first-line, dopamine replacement drug therapy, includes a number of drugs thatcan work in several distinct ways. First, the therapy may work to increase theamount of dopamine available in the brain. Levodopa is a precursor to dopaminethat crosses the blood–brain barrier and is converted to dopamine by the neurones(Schapira 2005, Jankovic 2008, Jankovic and Poewe 2012, Worth 2013, Kalia andLang 2015, Poewe et al 2017). While efficacious at reducing motor signs initially, itsefficacy tapers off with prolonged use. For example, over time (i.e. five to eightyears) involuntary dyskinetic, chorea-like, movements of the upper limbs developduring on-periods, when plasma levels of levodopa are high. During the off-periods,levodopa is not effective and patients may assume dystonic-like postures, often withpainful cramps, affecting predominately the lower limbs. Although the mechanismsare not clear, this loss of efficacy is thought to be due to the continued loss ofdopaminergic terminations in the striatum, together with a loss of sensitivity and/ordysregulation of the striatal dopaminergic receptors, all giving rise to variousabnormal neuronal responses. There are also issues of the variability in thegastrointestinal absorption and blood–brain barrier transport of levodopa, togetherwith its short half-life, over time (Schapira 2005, Jankovic 2008, Jankovic andPoewe 2012, Worth 2013, Kalia and Lang 2015, Oertel 2017, Poewe et al 2017).

Second, dopamine drug therapy may work to mimic the action of dopamine,activating dopamine receptors, for example D1 and D2, of neurones in the striatum.These drugs, which include the dopamine agonists such as bromocriptine andapomorphine, have a longer half-life than levodopa, making them attractive asadjunct treatments in patients with motor complications (i.e. dyskinesias). Ingeneral, while dopaminergic agonists are not as effective as levodopa in manypatients, they do not tend to induce motor complications as frequently, and may, insome cases, be the first treatment option in early-onset patients (Schapira 2005,Jankovic 2008, Jankovic and Poewe 2012, Worth 2013, Kalia and Lang 2015, Oertel2017, Poewe et al 2017).

Finally, some drugs, for example selegiline, rasagiline and safinamide, work onthe principal of arresting the breakdown of dopamine at the synapse, increasing itsavailability to post-synaptic neurones. Oxidation via monoamine oxidase B in glialcells is a key means by which dopamine is cleared from the synapse. Hence, theinhibition of this process prolongs and increases the availability of dopamine at thesynapse. These monoamine oxidase B inhibitors are often used in combination withlevodopa, but sometimes by themselves (Schapira 2005, Jankovic 2008, Jankovicand Poewe 2012, Worth 2013, Kalia and Lang 2015, Poewe et al 2017).

It should be noted that the many non-motor symptoms of the disease, from sleepdisorders to constipation, that result from a loss of non-dopaminergic neurones (seesections above on signs and symptoms and pathophysiology), do not necessarilyrespond well to dopamine drug therapy. Indeed, some of these symptoms may evenbe aggravated by this form of drug therapy (Schapira 2005, Jankovic 2008, Jankovicand Poewe 2012, Worth 2013, Kalia and Lang 2015, Oertel 2017, Poewe et al 2017).

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1.7.2 Surgical treatment: deep brain stimulation at high frequency

Neurosurgical intervention is reserved as a last-line treatment, after the efficacy ofthe dopamine replacement drug therapy diminishes and side effects, namelydyskinesias, develop. The basic principle of the surgery is to correct or adjust theabnormal activity of certain basal ganglia nuclei (i.e. globus pallidus, subthalamicnucleus, zona incerta) and/or the motor nuclei of the thalamus. The subthalamicnucleus, in particular, has been a most popular target in recent times, mainly becausethe majority of the signs of the disease, including tremor, bradykinesia, akinesia andrigidity, are improved after surgical intervention (Ashkan et al 2004, Benabid et al2009, Kalia and Lang 2015, Oertel 2017, Poewe et al 2017).

Neurosurgeons have used either destructive lesions, using heated electrodes orvarious toxins, or more recently, deep brain stimulation at high frequency (100–200Hz; creating a functional lesion) to dampen the abnormal activity in these nuclei.In fact, nowadays, deep brain stimulation is by far and away the most common formof surgical intervention used for Parkinson’s disease (Ashkan et al 2004, Benabidet al 2009).

Despite its popularity, the precise mechanisms behind deep brain stimulation still,quite remarkably, remain unclear, even though it has been used for the best part of 30years by neurosurgeons on Parkinson’s disease patients (Ashkan et al 2004, Benabid etal 2009). There is some evidence for several contributing factors, however. Deep brainstimulation at high frequency may dissociate inputs and outputs within the targetnucleus and disrupt the abnormal circuitry of the basal ganglia–thalamic–cortical loopin Parkinson’s disease. There is also evidence for deep brain stimulation having aninhibitory response on the target nucleus, by either having a depolarisation block,inactivating voltage-gated currents and/or activating inhibitory afferents (Dostrovskyand Lozano 2002, Ashkan et al 2004, Benabid et al 2009, Deuschl and Agid 2013,Chiken and Nambu 2016, Kalia and Lang 2015, Oertel 2017, Poewe et al 2017).

Deep brain stimulation at high frequency has been very effective in treating themotor signs of the disease in patients. Indeed, bilateral deep brain stimulation of thesubthalamic nucleus results in substantial improvements in motor scores (50–60%),together with reductions of dopamine replacement drug therapy dose (∼60%); pallidalstimulations manifest in similar motor improvements, but the reductions in drug doseare often less. In addition, the reduction in drug dose after subthalamic stimulationsleads to large reductions in dyskinesias and off-periods (60–70%). It should be notedthat patientswho have a good initial response to dopamine drug therapy, are in general,all the more likely to have a good response to deep brain stimulation (Dostrovsky andLozano 2002, Ashkan et al 2004, Benabid et al 2009, Deuschl and Agid 2013, Chikenand Nambu 2016, Kalia and Lang 2015, Oertel 2017, Poewe et al 2017).

1.8 Neuroprotection and future treatments1.8.1 Neuroprotection basics

The key feature of any therapeutic treatment deemed to be neuroprotective lies in itsability to preserve or enhance effectively the survival of neurones from distress or

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damage, after either vascular accident, trauma, toxic insult or genetic mutation. Adamaged neurone undergoes a series of stages before it dies (Schapira et al 2014). Inthe first instance, the neurone suffers intrinsic damage, perhaps as a result of theinteraction between its genetics and environment, a compromised blood supply ortrauma. At this stage, the neurone may not show any sign of dysfunction,presumably because its own intrinsic self-protective mechanisms maintain a levelof normal function. Over time, however, and with an increase in insult severity, theseintrinsic protective mechanisms become less effective and the neurone starts todysfunction and shows pathology, leading ultimately to its death. At each stage ofthis process, in particular during the early stages that involve the contributions of thegenetics of the neurone and its intrinsic protective mechanisms, the damagedneurone is open to therapeutic intervention (Schapira and Tolosa 2010, Schapiraet al 2014). Indeed, many of the more recent potential neuroprotective treatmentshave targeted these early stages for repair and protection (Olanow et al 2008, 2009,Schapira and Tolosa 2010, Schapira 2011, Stocchi and Olanow 2013, Schapira et al2014, Kalia et al 2015, Oertel 2017, Poewe et al 2017, Torres et al 2017).

The gold-standard measure of neuroprotection for any putative agent is a post-mortem analysis of the number of surviving neurones; how does neuronal number inthe treated group compare to that in the un-treated group, as well as in the control(i.e. normal) group? With regard to Parkinson’s disease, the region targeted foranalysis of neuronal number, thereby providing the gold-standard, has been themain zone of pathology of the disease, the SNc. Although some studies have usedmethods such as retrograde-tracing (Björklund et al 1997) and in situ hybridisation(Javoy-Agid et al 1990), the majority of previous studies have used two mainmethods to identify and count the neurones in the SNc, either by tyrosinehydroxylase immunohistochemistry or by routine Nissl staining histology (Javoy-Agid et al 1990, Jackson-Lewis et al 1995, Björklund et al 1997). Of these twomethods, tyrosine hydroxylase immunohistochemistry is by far the most common(e.g. Yoon et al 2007, Wallace et al 2007, Ashkan et al 2007, Luquin and Mitrofanis2008, Ma et al 2009, Tajiri et al 2010, Lau et al 2011, Gerecke et al 2010, 2012, Shawet al 2010, Peoples et al 2012a, Sung et al 2012, Tuon et al 2012, Real et al 2013,2017, Moro et al 2013, 2014, 2016, Johnstone et al 2014, Reinhart et al 2014, 2016a,2016b, 2017, El Massri et al 2016a, Jang et al 2017). It labels healthy neuronesexpressing their dopaminergic phenotype, thereby providing an index of function ofthe dopaminergic neurone. It provides the definitive way to identify the dopami-nergic neurones within the region. This type of analysis has often been referred to asfunctional neuroprotection. Its one disadvantage is that there is often a smallproportion of neurones—perhaps those not as extensively damaged by the parkin-sonian insult—that lose initial expression of the antigen and phenotype, but then re-express it at a later period (Jackson-Lewis et al 1995, Björklund et al 1997),presumably using self-protective mechanisms (see above).

Notwithstanding this small number, the majority of neurones that lose theirexpression of tyrosine hydroxylase will eventually undergo degeneration (Jackson-Lewis et al 1995, Björklund et al 1997). Nissl staining, on the other hand, labels allneurones regardless of their phenotypic expression, providing an index of whether

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the neurone is still present and alive (Wallace et al 2007, Ma et al 2009, Darlot et al2016). This type of analysis has been referred to as true neuroprotection because itrelates to an actual increase in neuronal survival and not just a rescue of thedopaminergic phenotype. The clear disadvantage of this method is that it is not adefinitive marker for the dopaminergic neurones in the region. Hence, during ananalysis of neuronal number, other functional types of neurones in the region maybe counted. For example, together with the dopaminergic neurones, the SNc hasbeen described to house a population of GABAergic neurones as well (Parent 1996,Blandini et al 2000). A further disadvantage of Nissl staining is that it does notprovide an index of whether these neurones are still functionally active andproducing dopamine (Javoy-Agid et al 1990, Jackson-Lewis et al 1995, Björklundet al 1997). Taking all these factors together, the best paradigm for most studieswould be to use both methods of analysis, as to provide an overall picture ofneuroprotection, both functional and true (Jackson-Lewis et al 1995, Wallace et al2007, Ma et al 2009, Darlot et al 2016).

In addition to this gold-standard, many studies have used other, secondary (silver-standards) assessments of neuroprotection of a given agent. These include whetherthe agent prompts an improvement of the intrinsic neuronal mechanisms (e.g.stimulates mitochondrial function), increases the density of axonal terminations and/or preserves protein and enzyme expressions in the local neuronal environment(Olanow et al 2008, 2009, Schapira and Tolosa 2010, Schapira 2011, Stocchi andOlanow 2013, Schapira et al 2014, Kalia et al 2015, Oertel 2017, Poewe et al 2017,Torres et al 2017).

1.8.2 Neuroprotective versus symptomatic treatments?

At this point, a distinction should be made between a neuroprotective treatment, onethat enhances the survival of a neurone, and a symptomatic treatment, one thatstimulates the functional activity of a neurone, with no impact on its survival. Adistressed or damaged neurone may function quite well, indeed may be stimulatedtherapeutically to do so, up until the last few stages of its survival. Symptomatictreatments may also stimulate other neurones, those not undergoing damagedirectly, to produce a range of compensatory functional and/or behavioural out-comes. In essence, an improvement in neuronal function and overall behaviour (e.g.locomotion) does not necessarily reflect an improvement in neuronal survival(Olanow et al 2008, 2009, Schapira and Tolosa 2010, Schapira 2011, Stocchi andOlanow 2013, Schapira et al 2014, Kalia et al 2015, Oertel 2017, Poewe et al 2017,Torres et al 2017).

In relation to Parkinson’s disease, the current mainstay treatments—dopaminereplacement drug therapy and deep brain stimulation—are largely symptomaticrather than neuroprotective, in that they serve to enhance the functionality of theneurone rather than its survival. It should be noted that for both dopamine drugtherapy and deep brain stimulation, there is some evidence, albeit conflicting, forneuroprotection in animal models and even less evidence, even more conflicting, inpatients (Ashkan et al 2007, Wallace et al 2007, Charles et al 2008, Benabid et al

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2009, Kalia et al 2015, Oertel 2017, Poewe et al 2017, Torres et al 2017). In the caseof deep brain stimulation of the subthalamic nucleus, neuroprotection of dopami-nergic neurones may occur after the glutamatergic inputs, and hence excitotoxicityfrom this nucleus are reduced. It has been suggested that, because of the relativelylow morbidity rates of deep brain stimulation surgery, patients could be offered thistreatment earlier in the disease, to improve the magnitude of neuroprotection of theremaining neurones, giving them a better chance of survival. The general consensusamong researchers is that the less damage a neurone or nucleus has suffered by thedisease process, then the more chance a treatment has to save them. This factor maywell improve the magnitude of neuroprotection evident by deep brain stimulation(Ashkan et al 2007, Charles et al 2008, Benabid et al 2009).

1.8.3 Why no neuroprotective treatment for patients?

The reasons why the quest for an effective neuroprotective treatment in Parkinson’sdisease has remained so elusive over the years are many and varied and have beensuggested to include the following. First, that the cause (and precise pathology) ofthe disease in patients is not known and, up until then, finding a treatment tocounteract or protect against it, is extremely difficult. Hence, in patients, a detailedmap to the whereabouts of the ‘holy grail’ has yet to be discovered. There are someclues as to where to look however, namely at the genetics and the intrinsic protectivemechanisms of the damaged neurones.

Second, that the disease is heterogenous in patients, with several sub-types beingidentified. In particular, there are many genotypes and multiple intrinsic mecha-nisms that underlie the pathology of the disease, contributing to a varied phenotype.Therefore, some treatments may work better in some patients compared to othersand a so-called single ‘magic-bullet’ neuroprotective treatment may be wishfulthinking. A cocktail of treatments, to cover a number of different angles of thedisease, appears to be a more likely outcome (Kalia et al 2015).

Third, that diagnosis in patients is usually made after a considerable and variableamount of neuronal degeneration has occurred already, making a common andsystematic start- and end-point of treatment (i.e. disease staging) extremelyproblematic.

Fourth, that defining an appropriate dose or method of application of any givenneuroprotective agent in patients with such a varied disease phenotype is less thanideal, even with careful patient selection (Olanow et al 2008, 2009, Schapira andTolosa 2010, Schapira 2011, Stocchi and Olanow 2013, Schapira et al 2014, Kaliaet al 2015, Oertel 2017, Poewe et al 2017, Torres et al 2017).

Fifth, that a single perfect animal model, one that encompasses the heterogeneity,as well as the patterns and progression of neuronal death in Parkinson’s disease, isnot available currently. However, it is commonly the case than any putativeneuroprotective treatment is tested in a number of animal models of the disease,from toxin-induced to transgenic, before proceeding to clinical trial in patients(Olanow et al 2008, 2009, Schapira and Tolosa 2010, Schapira 2011, Stocchi andOlanow 2013, Schapira et al 2014, Kalia et al 2015, Oertel 2017, Poewe et al 2017,

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Torres et al 2017). Nevertheless, finding an effective neuroprotective treatment in ananimal model remains somewhat easier than in patients, mainly because of thefollowing reasons; the cause of disease is induced in animals and thus there is muchless phenotypic variation; laboratory animals are far more homogeneous; the start-and end-points of treatment are much easier to define in animals, hence the keyfeature of prior neuronal degeneration (i.e. disease staging) is known; defining anappropriate dose or method of application, in such a homogeneous cohort, is far lessfraught with pit-falls in animal models, and the assessment or measure of neuro-protection is far more accurate in animals (Olanow et al 2008, 2009, Schapira andTolosa 2010, Schapira 2011, Stocchi and Olanow 2013, Schapira et al 2014, Kaliaet al 2015, Oertel 2017, Poewe et al 2017, Torres et al 2017).

Finally, the gold-standard measure of neuroprotection, post-mortem analyses ofneuronal number, although undertaken with ease in experimental animal models ofthe disease, has proved near impossible in patients. The same can be said for thesilver-standard measures, namely assessments of intrinsic neuronal mechanisms,density of axonal terminations and protein and enzyme expressions. These haveproved far more difficult in patients than in animal models. For this reason, othermeasures of so-called neuroprotection (bronze- and brass-standards) have beenattempted in patients. These include a measure of dopamine neurotransmissionusing functional imaging (e.g. with positron emission tomography scans), assessingrelatively high resolution anatomical imaging of basal ganglia nuclei, measuringprotein levels in blood serum (e.g. growth factors), undertaking long-term clinicalassessment of motor function with a Unified Parkinson’s Disease Rating Scale,particularly during a delayed-start, before treatment has started, and an extendedwashout period, after the treatment has stopped. Although each of these approachescan provide, and indeed have provided, useful information, they all suffer in thatthey do not offer the conclusive evidence for neuroprotection, as would say, a post-mortem analysis. What would help the development of a neuroprotective treatmentenormously would be the discovery of a distinct biomarker, one that offers anobjective measure of the phenotype and state of the disease. Such a marker could beused also to determine a more precise diagnosis and to track the progression of thedisease, with or without treatment (Olanow et al 2008, 2009, Schapira and Tolosa2010, Schapira 2011, Stocchi and Olanow 2013, Schapira et al 2014, Kalia et al2015, Oertel 2017, Poewe et al 2017, Torres et al 2017).

1.8.4 Future treatments

In terms of the future, there is a real need for the development of a neuroprotectivetreatment for Parkinson’s disease patients. In many animal models of the diseasehowever, there have been countless pharmaceutical and herbal agents that have beenreported to be neuroprotective. These agents are diverse, ranging from many typesof drugs to coenzyme Q10 (Olanow et al 2008, Kalia et al 2015), and from caffeine(Kolahdouzan and Hamadeh 2017) to various plant extracts (Abushouk et al 2017).There have also been several surgical approaches tackling the issue of neuro-protection, for example, introducing viral vectors to induce the expression of growth

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factors or neurotransmitter phenotype (McBride and Kordower 2002, Kordowerand Bjorklund 2013, Kalia and Lang 2015, Oertel 2017, Poewe et al 2017, Torreset al 2017). Unfortunately, in each case, the translation from the experimentalfindings in the laboratory to the patients in the clinic has been largely disappointing:for the most part, any given neuroprotective agent undergoing clinical trial has notprogressed past the very rigorous later phases, which include placebo controls. Someof the reasons for these failures have been considered above.

Notwithstanding these issues of translation from the laboratory to the clinic thatare faced currently, there should be a continued push to develop new methods tostop or slow down the pathology of the disease. Indeed, at present, there are severalavenues of exploration being undertaken. For example, despite the see-saw of highsand lows suffered by the growth factor GDNF in Parkinson’s disease, from the earlypromising laboratory findings to the failure at the clinical trial level, there is acontinued drive to develop this approach further. There are ongoing studiesdeveloping improved means of viral vector technology and delivery, together witha better understanding of how GDNF offers neuroprotection and promotes recoveryin neurones (McBride and Kordower 2002, Kordower and Bjorklund 2013, Kaliaand Lang 2015, Poewe et al 2017, Torres et al 2017, Whone et al 2019). There arealso investigations into using gene therapy (Witt and Marks 2011) to increasetyrosine hydroxylase expression leading to higher dopamine levels within thestriatum (Björklund et al 2009), together with inducing inhibitory GABA expressionwithin the subthalamic nucleus to reduce its output overactivity (LeWitt et al 2011).The foetal transplantation programme, which also suffered from a failure at clinicaltrial level (due to limited clinical improvement and the development of dyskinesias inpatients: Olanow et al 2003) and negative findings in subsequent post-mortemstudies (namely, a spread of Lewy body pathology into the transplanted tissue;Brundin and Kordower 2012) after early promise (Lindvall et al 1990), is also beingdeveloped further on patients (Barker et al 2015). There are also explorations intotargeting the α-synuclein aggregates directly with the development of variousimmunological approaches (Mandler et al 2014). Finally, there is of course thecontinued development of many pharmacological agents, from old ones like selegi-line, coenzyme Q and levodopa to newer ones like brain-penetrant dihydropyridinecalcium channel blockers (Linazasoro 2002, LeWitt 2006, Kalia et al 2015, Swartand Hurley 2016), in the hope that a neuroprotective effect can be found. Taken alltogether, these experimental approaches offer the prospect of changing the course ofthe disease and provide hope for the future.

1.8.5 Summary

Parkinson’s disease is a complex neurodegenerative disorder that affects a selectgroup of neurones across the brain, in particular, the dopaminergic neurones of themidbrain. The factors triggering the degeneration of these neurones are, for the mostpart, unclear. The current mainstay of treatments for the disease—dopaminereplacement drug therapy and deep brain stimulation surgery—are largely sympto-matic, in that they aim to maintain and/or increase the level of functional

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dopaminergic transmission in the brain. They do not, unfortunately, stop or slow thedegeneration of the neurones. As it stands, there is no effective treatment that isdisease-modifying or neuroprotective. Hence, the discovery and development ofsuch a treatment should be the principal factor driving research programmes into thedisease.

Although there are many endeavours in the pipeline, many of which are invasive,for the patients of tomorrow, attention should be drawn to the existence of twobeneficial, potentially neuroprotective, therapies that are on offer to patients today.These include the dynamic duo of exercise and light (i.e. photobiomodulation) thattogether could form a powerful combined therapy with many positive outcomes forpatients. The chapters that follow will consider the wide ranging benefits offered bythese two treatments in both animal models of the disease and in patients. A focuswill be on the cellular mechanisms behind each of these therapies, on how they maywork to provide beneficial outcomes.

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