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Pathology of behavior in PD: What is known and what is not?

Open AccessPublished:December 30, 2016DOI:https://doi.org/10.1016/j.jns.2016.12.062

      Highlights

      • Abnormal behaviors in PD manifest as an outcome of multi-level system dysfunction.
      • Many neurotransmitter pathways are disrupted in PD causing global network dysfunction.
      • A greater pathological understanding of PD behavior is needed to improve treatment.

      Abstract

      Abnormal behavior in Parkinson's disease (PD) stems from a complex orchestration of impaired neural networks that result from PD-related neurodegeneration across multiple levels. Typically, cellular and tissue abnormalities generate neurochemical changes and disrupt specific regions of the brain, in turn creating impaired neural circuits and dysfunctional global networks. The objective of this chapter is to provide an overview of the array of pathological changes that have been linked to different behavioral symptoms of PD such as depression, anxiety, apathy, fatigue, impulse control disorders, psychosis, sleep disorders and dementia.

      Keywords

      1. Overview of pathology in PD

      The pathology underlying Parkinson's disease is not fully understood. Whilst the Braak staging model has attempted to describe the progression of Lewy body pathology [
      • Braak H.
      • Ghebremedhin E.
      • Rüb U.
      • Bratzke H.
      • Del Tredici K.
      Stages in the development of Parkinson's disease-related pathology.
      ], the precise interplay between structural and functional changes across multiple neurotransmitter pathways and inter-related networks leads to a complex array of clinical features. These dysfunctional global networks [
      • Caviness J.N.
      Pathophysiology of Parkinson's disease behavior - a view from the network.
      ] manifest with a wide range of abnormal behaviors in Parkinson's disease (PD) that often coexist and impact negatively on quality of life. The objective of this chapter is to provide an overview of the current state of knowledge regarding the pathological changes that have been linked to behavioral abnormalities in PD.

      2. Pathological mechanisms underlying behaviors in PD

      2.1 Neuropsychiatric symptoms

      Certain neuropsychiatric symptoms can present at different stages of the disease and thus may reflect distinct mechanisms manifesting with the same clinical presentation. For example, a number of epidemiological studies have highlighted the onset of late life mood disorder, typically anxiety or depression as a prodromal ‘risk factor’ for the development of PD [
      • Aarsland D.
      • Marsh L.
      • Schrag A.
      Neuropsychiatric symptoms in Parkinson's disease.
      ,
      • Burn D.J.
      • Landau S.
      • Hindle J.V.
      • Samuel M.
      • Wilson K.C.
      • Hurt C.S.
      • et al.
      Parkinson's disease motor subtypes and mood.
      ,
      • Prediger R.D.S.
      • Matheus F.C.
      • Schwarzbold M.L.
      • Lima M.M.S.
      • Vital M.a.B.F.
      Anxiety in Parkinson's disease: a critical review of experimental and clinical studies.
      ,
      • Weisskopf M.G.
      • Chen H.
      • Schwarzschild M.A.
      • Kawachi I.
      • Ascherio A.
      Prospective study of phobic anxiety and risk of Parkinson's disease.
      ,
      • Ishihara L.
      • Brayne C.
      A systematic review of depression and mental illness preceding Parkinson's disease.
      ]. By way of contrast, some patients can experience anxiety and depression as part of a ‘wearing off’ phenomenon [
      • Leentjens A.F.G.
      • Dujardin K.
      • Marsh L.
      • Martinez-Martin P.
      • Richard I.H.
      • Starkstein S.E.
      Anxiety and motor fluctuations in Parkinson's disease: a cross-sectional observational study.
      ,
      • Maricle R.A.
      • Nutt J.G.
      • Carter J.H.
      Mood and anxiety fluctuation in Parkinson's disease associated with levodopa infusion: preliminary findings.
      ]. This implies that disparate mechanisms such as the prodromal loss of serotonergic/noradrenergic cells in the brainstem can cause similar clinical features to those presumably arising from a relatively hypo-dopaminergic state [
      • de la Fuente-Fernández R.
      Imaging of dopamine in PD and implications for motor and neuropsychiatric manifestations of PD.
      ,
      • Ballanger B.
      • Poisson A.
      • Broussolle E.
      • Thobois S.
      Functional imaging of non-motor signs in Parkinson's disease.
      ]. Furthermore, such neuropathological contributions may coexist and PET studies in patients with established PD have demonstrated the potential relationship between affective symptoms and brainstem serotonergic levels [
      • Pavese N.
      • Simpson B.S.
      • Metta V.
      • Ramlackhansingh A.
      • Chaudhuri K.R.
      • Brooks D.J.
      [18F]FDOPA uptake in the raphe nuclei complex reflects serotonin transporter availability. A combined [18F]FDOPA and [11C]DASB PET study in Parkinson's disease.
      ,
      • Maillet A.
      • Krack P.
      • Lhommée E.
      • Météreau E.
      • Klinger H.
      • Favre E.
      • et al.
      The prominent role of serotonergic degeneration in apathy, anxiety and depression in de novo Parkinson's disease.
      ]. Thus, behavioral symptoms are likely to represent a breadth of structural and functional neuropathology, which may also be impacted by other factors within individuals such as genetic influences and medications. Whilst trends have suggested that certain genetic polymorphisms (e.g. LRRK2) might also be associated with neuropsychiatric symptoms (i.e. anxiety and depression) [
      • Shanker V.
      • Groves M.
      • Heiman G.
      • Palmese C.
      • Saunders-Pullman R.
      • Ozelius L.
      • et al.
      Mood and cognition in leucine-rich repeat kinase 2 G2019S Parkinson's disease.
      ,
      • Goldwurm S.
      • Zini M.
      • Di Fonzo A.
      • De Gaspari D.
      • Siri C.
      • Simons E.J.
      • et al.
      LRRK2 G2019S mutation and Parkinson's disease: a clinical, neuropsychological and neuropsychiatric study in a large Italian sample.
      ,
      • Mirelman A.
      • Alcalay R.N.
      • Saunders-Pullman R.
      • Yasinovsky K.
      • Thaler A.
      • Gurevich T.
      • et al.
      Nonmotor symptoms in healthy Ashkenazi Jewish carriers of the G2019S mutation in the LRRK2 gene.
      ,
      • Campos F.L.
      • Carvalho M.M.
      • Cristovão A.C.
      • Je G.
      • Baltazar G.
      • Salgado A.J.
      • et al.
      Rodent models of Parkinson's disease: beyond the motor symptomatology.
      ], there has been no conclusive genetic correlations with visual hallucinations in PD [
      • Chang A.
      • Fox S.H.
      Psychosis in Parkinson's disease: epidemiology, pathophysiology, and management.
      ]. Additionally, the development of cognitive decline and dementia has been linked with the tau (MAPT) inversion polymorphism [
      • Goris A.
      • Williams-Gray C.H.
      • Clark G.R.
      • Foltynie T.
      • Lewis S.J.
      • Brown J.
      • et al.
      Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson's disease.
      ], however associations between dementia and the APOE4 allele, and LRRK2 gene remain controversial [
      • Shanker V.
      • Groves M.
      • Heiman G.
      • Palmese C.
      • Saunders-Pullman R.
      • Ozelius L.
      • et al.
      Mood and cognition in leucine-rich repeat kinase 2 G2019S Parkinson's disease.
      ,
      • Ezquerra M.
      • Campdelacreu J.
      • Gaig C.
      • Compta Y.
      • Muñoz E.
      • Martí M.J.
      • et al.
      Lack of association of APOE and tau polymorphisms with dementia in Parkinson's disease.
      ]. In the following sections, we will provide a summary based on evidence from the current literature and attempt to describe the hierarchical mechanisms that underlie neuropsychiatric behaviors.

      2.1.1 Depression and anxiety

      A seven-fold loss of nigral neurons has been found in post-mortem brains from depressed PD patients compared to non-depressed PD patients [
      • Frisina P.G.
      • Haroutunian V.
      • Libow L.S.
      The neuropathological basis for depression in Parkinson's disease.
      ]. In addition, many studies have found strong associations between depressive and anxiety symptoms and the decreased binding to dopamine transporters in the striatum [
      • Weintraub D.
      • Newberg A.B.
      • Cary M.S.
      • Siderowf A.D.
      • Moberg P.J.
      • Kleiner-Fisman G.
      • et al.
      Striatal dopamine transporter imaging correlates with anxiety and depression symptoms in Parkinson's disease.
      ,
      • Kaasinen V.
      • Nurmi E.
      • Bergman J.
      • Eskola O.
      • Solin O.
      • Sonninen P.
      • et al.
      Personality traits and brain dopaminergic function in Parkinson's disease.
      ,
      • Remy P.
      • Doder M.
      • Lees A.
      • Turjanski N.
      • Brooks D.
      Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system.
      ,
      • Tiihonen J.
      • Kuikka J.
      • Bergström K.
      • Lepola U.
      • Koponen H.
      • Leinonen E.
      Dopamine reuptake site densities in patients with social phobia.
      ,
      • Schneier F.R.
      • Liebowitz M.R.
      • Abi-Dargham A.
      • Zea-Ponce Y.
      • Lin S.H.
      • Laruelle M.
      Low dopamine D(2) receptor binding potential in social phobia.
      ,
      • Erro R.
      • Pappatà S.
      • Amboni M.
      • Vicidomini C.
      • Longo K.
      • Santangelo G.
      • et al.
      Anxiety is associated with striatal dopamine transporter availability in newly diagnosed untreated Parkinson's disease patients.
      ]. Thus, dysregulation of frontostriatal and mesocorticolimbic dopaminergic circuits have been suggested to play a key role in depression and anxiety in PD [
      • Weintraub D.
      • Newberg A.B.
      • Cary M.S.
      • Siderowf A.D.
      • Moberg P.J.
      • Kleiner-Fisman G.
      • et al.
      Striatal dopamine transporter imaging correlates with anxiety and depression symptoms in Parkinson's disease.
      ,
      • O'Callaghan C.O.
      • Shine J.M.
      • Lewis S.J.G.
      • Hornberger M.
      Neuropsychiatric symptoms in Parkinson's disease: fronto-striatal atrophy contributions.
      ,
      • Castrioto A.
      • Thobois S.
      • Carnicella S.
      • Maillet A.
      • Krack P.
      Emotional manifestations of PD: neurobiological basis.
      ]. However, in parallel greater pathology has also been suggested in the serotonergic raphe nucleus [
      • Paulus W.
      • Jellinger K.
      The neuropathologic basis of different subgroups of Parkinson's disease.
      ,
      • Becker T.
      • Becker G.
      • Seufert J.
      • Hofmann E.
      • Lange K.W.
      • Naumann M.
      • et al.
      Parkinson's disease and depression: evidence for an alteration of the basal limbic system detected by transcranial sonography.
      ], as well as the noradrenergic locus coeruleus [
      • Braak H.
      • Ghebremedhin E.
      • Rüb U.
      • Bratzke H.
      • Del Tredici K.
      Stages in the development of Parkinson's disease-related pathology.
      ,
      • Frisina P.G.
      • Haroutunian V.
      • Libow L.S.
      The neuropathological basis for depression in Parkinson's disease.
      ], which both heavily innervate corticolimbic regions involved in integrating anxious responses and emotional states [
      • Millan M.J.
      The neurobiology and control of anxious states.
      ]. Although limited research has examined this at the microscopic level, studies have reported evidence for the increased binding of serotonin transporters and reduced postsynaptic serotonin 1A receptor density within limbic regions in depressed PD patients [
      • Boileau I.
      • Warsh J.
      • Guttman M.
      • Saint-Cyr J.
      • McCluskey T.
      • Rusjan P.
      • et al.
      Elevated serotonin transporter binding in depressed patients with Parkinson's disease: a preliminary PET study with [11C]DASB.
      ,
      • Ballanger B.
      • Klinger H.
      • Eche J.
      • Lerond J.
      • Vallet A.E.
      • Le Bars D.
      • et al.
      Role of serotonergic 1A receptor dysfunction in depression associated with Parkinson's disease.
      ,
      • Politis M.
      • Wu K.
      • Loane C.
      • Turkheimer F.
      • Molloy S.
      • Brooks D.J.
      • et al.
      Depressive symptoms in PD correlate with higher 5-HTT binding in raphe and limbic structures.
      ]. Furthermore, PD patients who carried the short allele for the serotonin transporter scored significantly higher on anxiety scales than non-carriers [
      • Menza M.A.
      • Palermo B.
      • DiPaola R.
      • Sage J.
      • Ricketts M.
      Depression and anxiety in Parkinson's disease: possible effect of genetic variation in the serotonin transporter.
      ]. In addition, an increased incidence of anxiety and depression has also been correlated with lower dopamine/noradrenaline transporter binding in the locus coeruleus in PD [
      • Remy P.
      • Doder M.
      • Lees A.
      • Turjanski N.
      • Brooks D.
      Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system.
      ]. Interestingly, research studying de novo PD patients (i.e. those who have not begun dopaminergic therapy) has highlighted that treatment and/or disease progression may exacerbate the disruption of non-dopaminergic pathways [
      • Eskow Jaunarajs K.L.
      • Angoa-Perez M.
      • Kuhn D.M.
      • Bishop C.
      Potential mechanisms underlying anxiety and depression in Parkinson's disease: consequences of l-DOPA treatment.
      ,
      • Kuhn W.
      • Muller T.
      • Gerlach M.
      • Sofic E.
      • Fuchs G.
      • Heye N.
      • et al.
      Depression in Parkinson's disease: biogenic amines in CSF of “de novo” patients.
      ]. This work has suggested that serotonergic and noradrenergic neurons might act as surrogates for the dopaminergic system, by taking up exogenous levodopa and converting it to dopamine and then releasing it, at the expense of its normal function [
      • Carta M.
      • Carlsson T.
      • Kirik D.
      • Björklund A.
      Dopamine released from 5-HT terminals is the cause of l-DOPA-induced dyskinesia in parkinsonian rats.
      ,
      • Arai A.
      • Tomiyama M.
      • Kannari K.
      • Kimura T.
      • Suzuki C.
      • Watanabe M.
      • et al.
      Reuptake of l-DOPA-derived extracellular DA in the striatum of a rodent model of Parkinson's disease via norepinephrine transporter.
      ,
      • Eskow K.L.
      • Dupre K.B.
      • Barnum C.J.
      • Dickinson S.O.
      • John Y.
      • Bishop C.
      The role of the dorsal raphe nucleus in the development, expression and treatment of LID in hemiparkinsonian rats.
      ]. This notion suggests that chronic levodopa treatment may interact with non-dopaminergic systems, creating a paucity of serotonin and noradrenaline which in turn may contribute to depression and anxiety in PD.
      Reflecting the disruption of dopaminergic, serotonergic and noradrenergic circuits in PD patients with depression and/or anxiety, it is not surprising that gray matter atrophy [
      • O'Callaghan C.O.
      • Shine J.M.
      • Lewis S.J.G.
      • Hornberger M.
      Neuropsychiatric symptoms in Parkinson's disease: fronto-striatal atrophy contributions.
      ,
      • Feldmann A.
      • Illes Z.
      • Kosztolanyi P.
      • Illes E.
      • Mike A.
      • Kover F.
      • et al.
      Morphometric Changes of Gray Matter in Parkinson's Disease With Depression: A Voxel-based Morphometry Study.
      ,
      • Surdhar I.
      • Gee M.
      • Bouchard T.
      • Coupland N.
      • Malykhin N.
      • Camicioli R.
      Intact limbic-prefrontal connections and reduced amygdala volumes in Parkinson's disease with mild depressive symptoms.
      ,
      • van Mierlo T.J.
      • Chung C.
      • Foncke E.M.
      • Berendse H.W.
      • van den Heuvel O.A.
      Depressive symptoms in Parkinson's disease are related to decreased hippocampus and amygdala volume.
      ,
      • Cardoso E.F.
      • Maia F.M.
      • Fregni F.
      • Myczkowski M.L.
      • Melo L.M.
      • Sato J.R.
      • et al.
      Depression in Parkinson's disease: convergence from voxel-based morphometry and functional magnetic resonance imaging in the limbic thalamus.
      ] as well as white matter reductions [
      • Kostić V.
      • Agosta F.
      • Petrović I.
      • Galantucci S.
      • Spica V.
      • Jecmenica-Lukic M.
      • et al.
      Regional patterns of brain tissue loss associated with depression in Parkinson disease.
      ,
      • Matsui H.
      • Nishinaka K.
      • Oda M.
      • Niikawa H.
      • Komatsu K.
      • Kubori T.
      • et al.
      Depression in Parkinson's disease: diffusion tensor imaging study.
      ,
      • Li W.
      • Liu J.
      • Skidmore F.
      • Liu Y.
      • Tian J.
      • Li K.
      White matter microstructure changes in the thalamus in Parkinson disease with depression: a diffusion tensor MR imaging study.
      ] have also been found across limbic areas (e.g. orbitofrontal cortex, prefrontal cortex, cingulate cortex, temporal lobe, thalamus, hippocampus and amygdala). Furthermore, metabolic changes, such as reductions in cerebral blood flow have been noted in frontal and anterior cingulate regions [
      • Ring H.A.
      • Bench C.J.
      • Trimble M.R.
      • Brooks D.J.
      • Frackowiak R.S.
      • Dolan R.J.
      Depression in Parkinson's disease. A positron emission study.
      ] as well as increased metabolism within the amygdala [
      • Huang C.
      • Ravdin L.D.
      • Nirenberg M.J.
      • Piboolnurak P.
      • Severt L.
      • Maniscalco J.S.
      • et al.
      Neuroimaging markers of motor and nonmotor features of Parkinson's disease: an 18f fluorodeoxyglucose positron emission computed tomography study.
      ].
      From a neural network perspective, reduced functional connectivity has been reported within the corticolimbic network in depressed PD patients, whereas increased functional connectivity has been noted within their limbic system [
      • Castrioto A.
      • Thobois S.
      • Carnicella S.
      • Maillet A.
      • Krack P.
      Emotional manifestations of PD: neurobiological basis.
      ,
      • Huang P.
      • Xuan M.
      • Gu Q.
      • Yu X.
      • Xu X.
      • Luo W.
      • et al.
      Abnormal amygdala function in Parkinson's disease patients and its relationship to depression.
      ,
      • Sheng K.
      • Fang W.
      • Su M.
      • Li R.
      • Zou D.
      • Han Y.
      • et al.
      Altered spontaneous brain activity in patients with parkinson's disease accompanied by depressive symptoms, as revealed by regional homogeneity and functional connectivity in the prefrontal-limbic system.
      ]. It has been proposed that such a pattern of disturbances may reflect an abnormal top-down control of emotional processing [
      • Hu X.
      • Song X.
      • Yuan Y.
      • Li E.
      • Liu J.
      • Liu W.
      • et al.
      Abnormal functional connectivity of the amygdala is associated with depression in Parkinson's disease.
      ]. Unfortunately, much of the research to date has primarily investigated depression in PD with less work on anxiety. Future research is therefore needed to fully understand the synergies and differences in pathology that exist between anxiety and depression, as well as trying to further understand whether their pathophysiological mechanisms change in response to treatment or in relation to the progression of other symptoms such as dementia.

      2.1.2 Apathy and fatigue

      Whilst some researchers have argued that apathy can be explained by diffuse cortical Lewy bodies as a result of the advanced stages in PD [
      • Pagonabarraga J.
      • Kulisevsky J.
      • Strafella A.P.
      • Krack P.
      Apathy in Parkinson's disease: clinical features, neural substrates, diagnosis, and treatment.
      ], it is more widely accepted that apathy can early in disease progression. In this circumstance researchers have proposed that apathy might be primarily associated with low dopaminergic tone in both the striatum and prefrontal cortex [
      • de la Fuente-Fernández R.
      Imaging of dopamine in PD and implications for motor and neuropsychiatric manifestations of PD.
      ,
      • Thobois S.
      • Ardouin C.
      • Lhommée E.
      • Klinger H.
      • Lagrange C.
      • Xie J.
      • et al.
      Non-motor dopamine withdrawal syndrome after surgery for Parkinson's disease: predictors and underlying mesolimbic denervation.
      ]. In support of the latter, greater dopaminergic denervation has been shown in de novo PD patients with apathy [
      • Santangelo G.
      • Vitale C.
      • Picillo M.
      • Cuoco S.
      • Moccia M.
      • Pezzella D.
      • et al.
      Apathy and striatal dopamine transporter levels in de-novo, untreated Parkinson's disease patients.
      ] and mesolimbic dopaminergic denervation has also been linked with developing apathy in PD [
      • Thobois S.
      • Ardouin C.
      • Lhommée E.
      • Klinger H.
      • Lagrange C.
      • Xie J.
      • et al.
      Non-motor dopamine withdrawal syndrome after surgery for Parkinson's disease: predictors and underlying mesolimbic denervation.
      ]. Additionally, gray matter atrophy in the prefrontal, parietal and cingulate cortices has been associated with higher levels of apathy [
      • Reijnders J.S.A.M.
      • Scholtissen B.
      • Weber W.E.J.
      • Aalten P.
      • Verhey F.R.J.
      • Leentjens A.F.G.
      Neuroanatomical Correlates of Apathy in Parkinson's Disease: A Magnetic Resonance Imaging Study Using Voxel-based Morphometry.
      ] and the nucleus accumbens has been shown to be atrophic in apathetic PD patients [
      • Carriere N.
      • Besson P.
      • Dujardin K.
      • Duhamel A.
      • Defebvre L.
      • Delmaire C.
      • et al.
      Apathy in Parkinson's disease is associated with nucleus accumbens atrophy: a magnetic resonance imaging shape analysis.
      ]. It should be noted that these findings have not been identified consistently and other studies comparing PD groups based on high and low apathy scores have failed to find any gray matter density differences [
      • Isella V.
      • Melzi P.
      • Grimaldi M.
      • Iurlaro S.
      • Piolti R.
      • Ferrarese C.
      • et al.
      Clinical, neuropsychological, and morphometric correlates of apathy in Parkinson's disease.
      ]. More research is needed in this area to fully understand the underlying mechanisms of motivation and how PD pathology might disrupt these networks in patients with apathy.
      There is growing evidence that a strong relationship exists between apathy and dementia in PD. Apathy is more common in PDD patients [
      • Lee W.-J.
      • Tsai C.-F.
      • Gauthier S.
      • Wang S.-J.
      • Fuh J.-L.
      The association between cognitive impairment and neuropsychiatric symptoms in patients with Parkinson's disease dementia.
      ] and represents an independent neuropsychiatric profile of PDD, separate from mood, agitation and psychosis [
      • Aarsland D.
      • Brønnick K.
      • Ehrt U.
      • De Deyn P.P.
      • Tekin S.
      • Emre M.
      • et al.
      Neuropsychiatric symptoms in patients with Parkinson's disease and dementia: frequency, profile and associated care giver stress.
      ]. Even a caregivers' report of patients' apathy has been suggested to determine those at risk for subsequently developing dementia in PD [
      • Fitts W.
      • Weintraub D.
      • Massimo L.
      • Chahine L.
      • Chen-Plotkin A.
      • Duda J.E.
      • et al.
      Caregiver report of apathy predicts dementia in Parkinson's disease.
      ]. Executive dysfunction has also been found to be worse in PD patients with apathy [
      • Santangelo G.
      • Vitale C.
      • Trojano L.
      • Longo K.
      • Cozzolino A.
      • Grossi D.
      • et al.
      Relationship between depression and cognitive dysfunctions in Parkinson's disease without dementia.
      ,
      • Zgaljardic D.J.
      • Borod J.C.
      • Foldi N.S.
      • Rocco M.
      • Mattis P.J.
      • Gordon M.F.
      • et al.
      Relationship between self-reported apathy and executive dysfunction in nondemented patients with Parkinson disease.
      ]. Notably, a recent study also suggested that fatigue might be related to executive dysfunction, since motor performance worsened over time in PD patients with fatigue during an attention-demanding externally cued task, compared to PD without fatigue, whilst deterioration of performance was not seen in either group in the un-cued motor task [
      • Martino D.
      • Tamburini T.
      • Zis P.
      • Rosoklija G.
      • Abbruzzese G.
      • Ray-Chaudhuri K.
      • et al.
      An objective measure combining physical and cognitive fatigability: correlation with subjective fatigue in Parkinson's disease.
      ].
      The neural underpinnings of fatigue are also unclear. A strong association has been made between apathy and fatigue [
      • Castrioto A.
      • Thobois S.
      • Carnicella S.
      • Maillet A.
      • Krack P.
      Emotional manifestations of PD: neurobiological basis.
      ], and both symptoms have been hypothesized to share a common pathology within the basal ganglia-limbic dopaminergic system [
      • Pagonabarraga J.
      • Kulisevsky J.
      • Strafella A.P.
      • Krack P.
      Apathy in Parkinson's disease: clinical features, neural substrates, diagnosis, and treatment.
      ,
      • Chaudhuri A.
      • Behan P.O.
      Fatigue and basal ganglia.
      ]. In support of this, fatigue has been shown to significantly improve with dopaminergic replacement therapy (i.e. rosagiline or dopamine agonists), although these improvements remains clinically [
      • Lim T.T.
      • Kluger B.M.
      • Rodriguez R.L.
      • Malaty I.A.
      • Palacio R.
      • Ojo O.O.
      • et al.
      Rasagiline for the symptomatic treatment of fatigue in Parkinson's disease.
      ]. Fatigue has also been associated with abnormal blood flow in the putamen and supplementary motor area, suggesting that abnormalities in the basal ganglia pathways may cause fatigue [
      • Chaudhuri A.
      • Behan P.O.
      Fatigue and basal ganglia.
      ]. There is also a small amount of evidence which suggests that serotonergic lesions in the ventral striatum, cingulate cortex and amygdala are correlated with fatigue [
      • Pavese N.
      • Metta V.
      • Bose S.K.
      • Chaudhuri K.R.
      • Brooks D.J.
      Fatigue in Parkinson's disease is linked to striatal and limbic serotonergic dysfunction.
      ]. However, to date fatigue remains one of the most understudied non-motor symptoms of PD with regards to its pathophysiology and treatment. Much more research is needed to explore the neural underpinnings and pathology underlying fatigue and how dissociable it is from apathy and depression.

      2.1.3 Impulse control disorders

      Treatment related abnormalities within the non-motor frontostriatal loops have been suggested to be primarily responsible for impulse control disorders (ICD) due to ‘excessive dopaminergic drive’ [
      • de la Fuente-Fernández R.
      Imaging of dopamine in PD and implications for motor and neuropsychiatric manifestations of PD.
      ]. This proposed pathogenesis is in keeping with studies which report greater release of dopamine within the ventral striatum after levodopa intake as well as increased dopamine D2/D3 receptor availability in the anterior cingulate cortex in PD patients with pathological gambling [
      • Steeves T.D.L.
      • Miyasaki J.
      • Zurowski M.
      • Lang A.E.
      • Pellecchia G.
      • Van Eimeren T.
      • et al.
      Increased striatal dopamine release in Parkinsonian patients with pathological gambling: a [11C] raclopride PET study.
      ,
      • Buckholtz J.W.
      • Treadway M.T.
      • Cowan R.L.
      • Woodward N.D.
      • Li R.
      • Ansari M.S.
      • et al.
      Dopaminergic network differences in human impulsivity.
      ,
      • Ray N.J.
      • Miyasaki J.M.
      • Zurowski M.
      • Ko J.H.
      • Cho S.S.
      • Pallencchia G.
      • et al.
      Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson's patients with medication-induced pathological gambling: a [11C] FLB-457 and PET study.
      ]. Likewise, reductions in gray matter volume have also been found in the frontal lobe in PD patients with ICDs [
      • Biundo R.
      • Formento-Dojot P.
      • Facchini S.
      • Vallelunga A.
      • Ghezzo L.
      • Foscolo L.
      • et al.
      Brain volume changes in Parkinson's disease and their relationship with cognitive and behavioural abnormalities.
      ] and functional neuroimaging data highlighted that PD patients with ICDs (i.e. problem gambling or compulsive shopping) showed reduced activation in the ventral striatum, anterior cingulate cortex and orbitofrontal cortex along with more risky behaviors [
      • Voon V.
      • Gao J.
      • Brezing C.
      • Symmonds M.
      • Ekanayake V.
      • Fernandez H.H.
      Dopamine agonists and risk: impulse control disorders in Parkinson's disease.
      ]. Taken together, regions that play an important role in risk evaluation, impulse control and response inhibition, as well as dysfunction within the reward circuit [
      • Voon V.
      • Gao J.
      • Brezing C.
      • Symmonds M.
      • Ekanayake V.
      • Fernandez H.H.
      Dopamine agonists and risk: impulse control disorders in Parkinson's disease.
      ] all seem to be related to ICDs in PD.

      2.1.4 Psychosis

      High densities of Lewy bodies, as well as plaques and tangles, have been found in a variety of areas throughout the brain in PD patients with hallucinations including frontal, parietal, and temporal areas, notably the amygdala and parahippocampus [
      • de la Fuente-Fernández R.
      Imaging of dopamine in PD and implications for motor and neuropsychiatric manifestations of PD.
      ,
      • Harding A.J.
      • Stimson E.
      • Henderson J.M.
      • Halliday G.M.
      Clinical correlates of selective pathology in the amygdala of patients with Parkinson's disease.
      ,
      • Harding A.J.
      • Broe G.A.
      • Halliday G.M.
      Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe.
      ,
      • Papapetropoulos S.
      • McCorquodale D.S.
      • Gonzalez J.
      • Jean-Gilles L.
      • Mash D.C.
      Cortical and amygdalar Lewy body burden in Parkinson's disease patients with visual hallucinations.
      ,
      • Jacobson S.A.
      • Morshed T.
      • Dugger B.N.
      • Baech T.G.
      • Hentz J.G.
      • Adler C.H.
      Plaques and tangles as well as Lewy-type alpha synucleinopathy are associated with formed visual hallucinations.
      ]. Likewise, cortical alpha-synuclein pathology can also be a major determinant for the onset of psychosis in PD [
      • de la Fuente-Fernández R.
      Imaging of dopamine in PD and implications for motor and neuropsychiatric manifestations of PD.
      ,
      • Chang A.
      • Fox S.H.
      Psychosis in Parkinson's disease: epidemiology, pathophysiology, and management.
      ]. Furthermore, several neurotransmitter systems (i.e. dopamine, serotonin, and acetylcholine) have also been implicated in PD psychosis [
      • Chang A.
      • Fox S.H.
      Psychosis in Parkinson's disease: epidemiology, pathophysiology, and management.
      ]. The dopaminergic system is considered to play a pivotal role, especially in the later stages of the disease, whereby an overflow of dopamine and overstimulation of mesocorticolimbic dopamine D2 receptors in the limbic and cortical areas have been suggested to produce psychosis in a similar way that motor dyskinesias are brought about [
      • Goetz C.G.
      • Tanner C.M.
      • Klawans H.L.
      Pharmacology of hallucinations induced by long-term drug therapy.
      ,
      • Wolters E.C.
      Dopaminomimetic psychosis in Parkinson's disease patients L diagnosis and treatment.
      ,
      • Moskovitz C.
      • Moses H.
      • Klawans H.L.
      Levodopa-induced psychosis: a kindling phenomenon.
      ]. Interestingly, amantadine whilst reducing dyskinesia in many patients can also trigger hallucinations in some but not all. These observations suggest that this NMDA antagonist may be influencing the neurobiology through a combination of dopaminergic and glutaminergic processes, which may be subject to other influences (e.g. genetic, medication combination/doses, other monoaminergic pathways) at the individual level. There has also been evidence that PD patients with hallucinations have increased serotonin A2 binding and receptor density in ventral visual pathways, as well within the dorsolateral prefrontal cortex, orbitofrontal cortex and insula [
      • Ballanger B.
      • Strafella A.P.
      • Van Eimeren T.
      • Zurowski M.
      • Rusjan P.
      • Houle S.
      Serotonin 2A receptors and visual hallucinations in Parkinson's disease.
      ]. Similar to the hypothesis put forward for mood disorders, increased serotonergic receptor function might reflect serotonergic neurons acting as false transmitters or compensatory postsynaptic serotonergic up-regulated from reduced dopamine or serotonin [
      • Chang A.
      • Fox S.H.
      Psychosis in Parkinson's disease: epidemiology, pathophysiology, and management.
      ]. A reduction in glutamate levels has also been noted in PD patients with psychosis, which might contribute to dopaminergic over activity [
      • Riederer P.
      • Lange K.W.
      • Kornhuber J.
      • Danielczyk W.
      Glutamatergic-dopaminergic balance in the brain. Its importance in motor disorders and schizophrenia.
      ]. This might explain amantadine's psychosis enhancing effect, however further research is needed to elucidate this point.
      Several neuroimaging studies have attempted to identify the underlying substrates of hallucinations in PD, however to date results remain inconsistent (for review – see [
      • Chang A.
      • Fox S.H.
      Psychosis in Parkinson's disease: epidemiology, pathophysiology, and management.
      ]). Greater atrophy has been reported in hallucinators across the visual processing and cognitive pathways compared to non-hallucinators [
      • Watanabe H.
      • Senda J.
      • Kato S.
      • Ito M.
      • Atsuta N.
      • Hara K.
      • et al.
      Cortical and subcortical brain atrophy in Parkinson's disease with visual hallucination.
      ]. Likewise, white matter reduction in the parahippocampus, posterior cingulate cortex and occipital areas were found in PD patients with hallucinations compared to non-hallucinators. Decreased metabolism in visual cortical areas has been reported frequently but is partly confounded by the coexistence of cognitive impairment [
      • Boecker H.
      • Ceballos-Baumann A.O.
      • Volk D.
      • Conrad B.
      • Forstl H.
      • Haussermann P.
      Metabolic alterations in patients with Parkinson disease and visual hallucinations.
      ,
      • Park H.K.
      • Kim J.S.
      • Im K.C.
      • Kim M.J.
      • Lee J.-H.
      • Lee M.C.
      Visual hallucinations and cognitive impairment in Parkinson's disease.
      ]. Increased functional connectivity in the default mode network [
      • Yao N.
      • Shek-Kwan Chang R.
      • Cheung C.
      • Pang S.
      • Lau K.K.
      • Suckling J.
      The default mode network is disrupted in Parkinson's disease with visual hallucinations.
      ,
      • Franciotti R.
      • Delli Pizzi S.
      • Perfetti B.
      • Tartaro A.
      • Bonanni L.
      • Thomas A.
      Default mode network links to visual hallucinations: a comparison between Parkinson's disease and multiple system atrophy.
      ], as well as reduced activation in prefrontal and cingulate cortex [
      • Watanabe H.
      • Senda J.
      • Kato S.
      • Ito M.
      • Atsuta N.
      • Hara K.
      • et al.
      Cortical and subcortical brain atrophy in Parkinson's disease with visual hallucination.
      ] has also been linked to hallucinations in PD. More recent work has highlighted the role of dysfunctional attentional networks that mediate visual and perceptual processing, which likely underpin hallucinations and psychosis in PD [
      • Shine J.M.
      • Muller A.J.
      • O'Callaghan C.
      • Hornberger M.
      • Halliday G.M.
      • Lewis S.J.
      Abnormal connectivity between the default mode and the visual system underlies the manifestation of visual hallucinations in Parkinson's disease: a task-based fMRI study.
      ,
      • Shine J.M.
      • O'Callaghan C.
      • Halliday G.M.
      • Lewis S.J.G.
      Tricks of the mind: visual hallucinations as disorders of attention.
      ,
      • Shine J.M.
      • Halliday G.M.
      • Naismith S.L.
      • Lewis S.J.G.
      Visual misperceptions and hallucinations in Parkinson's disease: dysfunction of attentional control networks?.
      ,
      • Shine J.M.
      • Halliday G.M.
      • Gilat M.
      • Matar E.
      • Bolitho S.J.
      • Carlos M.
      • et al.
      The role of dysfunctional attentional control networks in visual misperceptions in Parkinson's disease.
      ,
      • Lewis S.J.G.
      • Shine J.M.
      • Duffy S.
      • Halliday G.
      • Naismith S.L.
      Anterior cingulate integrity: executive and neuropsychiatric features in Parkinson's disease.
      ].

      2.2 Sleep disorders

      Cellular loss in PD has been documented in nearly all circadian control areas, especially neuronal networks governing the sleep-wake cycle [
      • Gunn D.G.
      • Naismith S.L.
      • Lewis S.J.G.
      Sleep disturbances in Parkinson disease and their potential role in heterogeneity.
      ,
      • Ondo W.G.
      Sleep/wake problems in Parkinson's disease: pathophysiology and clinicopathologic correlations.
      ,
      • Zhong G.
      • Naismith S.L.
      • Rogers N.L.
      • Lewis S.J.G.
      Sleep-wake disturbances in common neurodegenerative diseases: a closer look at selected aspects of the neural circuitry.
      ]. Thus, PD patients can often experience several sleep disorders including Rapid Eye Movement (REM) sleep behavior disorder (RBD); excessive daytime sleepiness (EDS); insomnia and Restless Legs Syndrome (RLS). Disturbed sleep in PD has been associated with alpha-synuclein pathology within locus coeruleus and raphe nuclei, as well as hypothalamic areas and subcortical/limbic areas such as the amygdala, thalamus, and enterorhinal cortex [
      • Ondo W.G.
      Sleep/wake problems in Parkinson's disease: pathophysiology and clinicopathologic correlations.
      ,
      • Kalaitzakis M.E.
      • Gentleman S.M.
      • Pearce R.K.
      Disturbed sleep in Parkinson's disease: anatomical and pathological correlates.
      ]. Widespread tau pathology has also been reported in PD cases with “more sleep problems” [
      • Kalaitzakis M.E.
      • Gentleman S.M.
      • Pearce R.K.
      Disturbed sleep in Parkinson's disease: anatomical and pathological correlates.
      ]. However, it is important to note that the pathological mechanisms underlying these sleep disorders remains for the most part unclear.
      Early degenerative processes in PD, as noted in the Braak staging model, disrupt the medullary and pontine circuits, which are important for controlling REM sleep atonia [
      • Mathis J.
      • Hess C.W.
      • Bassetti C.
      Isolated mediotegmental lesion causing narcolepsy and rapid eye movement sleep behaviour disorder: a case evidencing a common pathway in narcolepsy and rapid eye movement sleep behaviour disorder.
      ,
      • Provini F.
      • Vetrugno R.
      • Pastorelli F.
      • Lombardi C.
      • Plazzi G.
      • Marliani A.F.
      • et al.
      Status dissociatus after surgery for tegmental ponto-mesencephalic cavernoma: a state-dependent disorder of motor control during sleep.
      ] offering a possible explanation as to why RBD symptoms can present years before PD motor symptom onset [
      • Peever J.
      • Luppi P.-H.
      • Montplaisir J.
      Breakdown in REM sleep circuitry underlies REM sleep behavior disorder.
      ,
      • Iranzo A.
      • Tolosa E.
      • Gelpi E.
      • Molinuevo J.L.
      • Valldeoriola F.
      • Serradell M.
      • et al.
      Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study.
      ]. In keeping with this hypothesis, alpha-synuclein deposition and Lewy bodies have been reported in the subcoeruleus region in idiopathic RBD without PD [
      • Boeve B.F.
      • Silber M.H.
      • Saper C.B.
      • Ferman T.J.
      • Dickson D.W.
      • Parisi J.E.
      • et al.
      Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease.
      ,
      • García-Lorenzo D.
      • Longo-Dos Santos C.
      • Ewenczyk C.
      • Leu-Semenescu S.
      • Gallea C.
      • Quattrocchi G.
      • et al.
      The coeruleus/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson's disease.
      ,
      • Ehrminger M.
      • Latimier A.
      • Pyatigorskaya N.
      • Garcia-Lorenzo D.
      • Leu-Semenescu S.
      • Vidailhet M.
      • et al.
      The coeruleus/subcoeruleus complex in idiopathic rapid eye movement sleep behaviour disorder.
      ,
      • Boeve B.F.
      • Silber M.H.
      • Ferman T.J.
      • Lucas J.A.
      • Parisi J.E.
      Association of REM sleep behaviour disorder and neurodegenerative disease may reflect an underlying synucleinopathy.
      ]. Reduced striatal dopamine levels have also been noted in RBD patients, similar to that of PD [
      • Eisensehr I.
      • Linke R.
      • Noachtar S.
      • Schwarz J.
      • Gildehaus F.J.
      • Tatsch K.
      Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behaviour disorder - comparison with Parkinson's disease and controls.
      ,
      • Albin R.L.
      • Koeppe R.A.
      • Chervin R.D.
      • Consens F.B.
      • Wernette K.
      • Frey K.A.
      • et al.
      Decreased striatal dopaminergic innervation in REM sleep behavior disorder.
      ] and continuous loss of presynaptic dopaminergic function has also been reported over a 3-year longitudinal study of RBD patients [
      • Iranzo A.
      • Lomeña F.
      • Stockner H.
      • Valldeoriola F.
      • Vilaseca I.
      • Salamero M.
      • et al.
      Decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity as risk markers of synucleinopathy in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study [corrected].
      ,
      • Iranzo A.
      • Valldeoriola F.
      • Lomeña F.
      • Molinuevo J.L.
      • Serradell M.
      • Salamero M.
      • et al.
      Serial dopamine transporter imaging of nigrostriatal function in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study.
      ].
      Other data have implicated GABAergic, glutaminergic, serotonergic, noradrenergic, cholinergic and hypocretinergic systems in RBD [
      • Peever J.
      • Luppi P.-H.
      • Montplaisir J.
      Breakdown in REM sleep circuitry underlies REM sleep behavior disorder.
      ,
      • Kotagal V.
      • Albin R.L.
      • Muller M.L.
      • Koeppe R.A.
      • Chervin R.D.
      • Frey K.A.
      • et al.
      Symptoms of rapid eye movement sleep behavior disorder are associated with cholinergic denervation in Parkinson disease.
      ,
      • Brooks P.L.
      • Peever J.H.
      Identification of the transmitter and receptor mechanisms responsible for REM sleep paralysis.
      ,
      • Brooks P.L.
      • Peever J.H.
      Glycinergic and GABA(A)-mediated inhibition of somatic motoneurons does not mediate rapid eye movement sleep motor atonia.
      ,
      • Fenik V.B.
      • Davies R.O.
      • Kubin L.
      Noradrenergic, serotonergic and GABAergic antagonists injected together into the XII nucleus abolish the REM sleep-like depression of hypoglossal motoneuronal activity.
      ], due the impairment of brainstem structures in the pontine-tegmentum, which are also known to play an important role in modulating REM sleep. Whilst changes in gray and white matter of the thalamus and brainstem have been reported in RBD [
      • García-Lorenzo D.
      • Longo-Dos Santos C.
      • Ewenczyk C.
      • Leu-Semenescu S.
      • Gallea C.
      • Quattrocchi G.
      • et al.
      The coeruleus/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson's disease.
      ,
      • Ehrminger M.
      • Latimier A.
      • Pyatigorskaya N.
      • Garcia-Lorenzo D.
      • Leu-Semenescu S.
      • Vidailhet M.
      • et al.
      The coeruleus/subcoeruleus complex in idiopathic rapid eye movement sleep behaviour disorder.
      ,
      • Scherfler C.
      • Frauscher B.
      • Schocke M.
      • Iranzo A.
      • Gschliesser V.
      • Seppi K.
      • et al.
      White and gray matter abnormalities in idiopathic rapid eye movement sleep behavior disorder: a diffusion-tensor imaging and voxel-based morphometry study.
      ,
      • Unger M.M.
      • Belke M.
      • Menzler K.
      • Heverhagen J.T.
      • Keil B.
      • Stiasny-Kolster K.
      • et al.
      Diffusion tensor imaging in idiopathic REM sleep behavior disorder reveals microstructural changes in the brainstem, substantia nigra, olfactory region, and other brain regions.
      ,
      • Salsone M.
      • Cerasa A.
      • Arabia G.
      • Morelli M.
      • Gambardella A.
      • Mumoli L.
      • et al.
      Reduced thalamic volume in Parkinson disease with REM sleep behavior disorder: volumetric study.
      ], many neuroimaging results remain inconsistent and yet to be confirmed (see recent review [
      • Heller J.
      • Brcina N.
      • Dogan I.
      • Holtbernd F.
      • Romanzetti S.
      • Schulz J.B.
      • et al.
      Brain imaging findings in idiopathic REM sleep behavior disorder (RBD) - a systematic review on potential biomarkers for neurodegeneration.
      ]). A recent resting state study demonstrated reduced functional connectivity within the basal ganglia network in RBD patients (who did not manifest PD), which was remarkably similar to PD patients (although the presence of RBD was not assessed in the PD patients) [
      • Rolinski M.
      • Griffanti L.
      • Piccini P.
      • Roussakis A.A.
      • Szewczyk-krolikowski K.
      • Menke R.A.
      • et al.
      Basal Ganglia Dysfunction in Idiopathic REM Sleep Behaviour Disorder Parallels That in Early Parkinson's Disease.
      ]. Furthermore, a highly specific metabolic brain network, marked by metabolic increases in pallidothalamic, pontine and cerebellar regions and decreased activity in premotor and parietal regions, has been identified in PD and is associated with motor symptoms [
      • Eidelberg D.
      Metabolic brain networks in neurodegenerative disorders: a functional imaging approach.
      ]. Interestingly, this ‘motor related’ PD pattern has also been found to be elevated in RBD patients [
      • Wu P.
      • Yu H.
      • Peng S.
      • Dauvilliers Y.
      • Wang J.
      • Ge J.
      • et al.
      Consistent abnormalities in metabolic network activity in idiopathic rapid eye movement sleep behaviour disorder.
      ,
      • Holtbernd F.
      • Gagnon J.-F.
      • Postuma R.B.
      • Ma Y.
      • Tang C.C.
      • Feigin A.S.
      • et al.
      Abnormal metabolic network activity in REM sleep behavior disorder.
      ]. Whilst this field is still in its infancy nonetheless, it is becoming clear that RBD and PD overlap substantially in their pathology and may be an important target for future disease-modifying therapies delivered at the earliest possible time, since the majority of these patients develop one of the three alpha-synucleinopathies.
      EDS have been hypothesized to have a number of causes including exogenous medications, loss of dopamine, loss of norepinephrine and serotonin (alerting monoamines), loss of hypocretin pathways, loss of autonomic function, and loss of circadian control [
      • Ondo W.G.
      Sleep/wake problems in Parkinson's disease: pathophysiology and clinicopathologic correlations.
      ]. However, no specific pathological study has attempted to correlate dopamine cell loss, serotonergic or noradrenergic specifically with EDS whereas, a few studies have found marked reduction of CSF hypocretin, as occurs in narcolepsy [
      • Maeda T.
      • Nagata K.
      • Kondo H.
      • Kanbayashi T.
      Parkinson's disease comorbid with narcolepsy presenting low CSF hypocretin/orexin level.
      ]. Similarly, there is also relatively little data exploring insomnia and circadian disturbance in PD. Whilst a small number of studies have investigated alterations in the pattern of melatonin secretion in PD [
      • Fertl E.
      • Auff E.
      • Doppelbauer A.
      • Waldhauser F.
      Circadian secretion pattern of melatonin in de novo parkinsonian patients: evidence for phase-shifting properties of l-dopa.
      ,
      • Videnovic A.
      • Noble C.
      • Reid K.J.
      • Peng J.
      • Turek F.W.
      • Marconi A.
      • et al.
      Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease.
      ,
      • Breen D.P.
      • Vuono R.
      • Nawarathna U.
      • Fisher K.
      • Shneerson J.M.
      • Reddy A.B.
      • et al.
      Sleep and circadian rhythm regulation in early Parkinson disease.
      ] along with the impact of disease progression [
      • Fertl E.
      • Auff E.
      • Doppelbauer A.
      • Waldhauser F.
      Circadian secretion pattern of melatonin in Parkinson's disease.
      ] and dopaminergic medication [
      • Bolitho S.J.
      • Naismith S.L.
      • Rajaratnam S.M.W.
      • Grunstein R.R.
      • Hodges J.R.
      • Terpening Z.
      • et al.
      Disturbances in melatonin secretion and circadian sleep-wake regulation in Parkinson disease.
      ] more detailed studies are required to inform our understanding.
      Explorations of the pathophysiology of RLS in PD has mainly focused on homeostatic iron dysregulation in the brain. Specifically, previous studies have shown a reduction in iron stores in the striatum and substantia nigra of patients with idiopathic RLS [
      • Allen R.P.
      • Barker P.B.
      • Wehrl F.
      • Song H.K.
      • Earley C.J.
      MRI measurement of brain iron in patients with restless legs syndrome.
      ,
      • Connor J.R.
      Pathophysiology of restless legs syndrome: evidence for iron involvement.
      ]. However, PD is generally associated with increased iron levels in the basal ganglia structures and work comparing PD patients with and without RLS has not identified significant differences in iron deposition [
      • Kwon D.Y.
      • Seo W.K.
      • Yoon H.K.
      • Park M.H.
      • Koh S.B.
      • Park K.W.
      Transcranial brain sonography in Parkinson's disease with restless legs syndrome.
      ,
      • Ryu J.H.
      • Lee M.S.
      • Baik J.S.
      Sonographic abnormalities in idiopathic restless legs syndrome (RLS) and RLS in Parkinson's disease.
      ]. Although dopaminergic medications typically improve RLS, there has been little evidence of dopamine deficiency associated with RLS in PD. Furthermore, non-dopaminergic medications used to treat PD, such as anticholinergic, SSRI and anti-psychotics have been suggested to exacerbate RLS [
      • Ondo W.G.
      Sleep/wake problems in Parkinson's disease: pathophysiology and clinicopathologic correlations.
      ]. In sum, there are no clear pathologic similarities between PD and RLS to date.

      2.3 Dementia

      Parkinson's disease dementia (PDD), like many other behavioral symptoms described here, also has a complex and multifactorial pathogenesis, especially since it typically affects PD patients in the later disease stages. Although cortical Lewy body pathology (in the frontal, cingulate and hippocampal areas) has been argued to be the primary pathological substrate, amyloid beta plaques and neurofibrillary tangles have also been found to be associated with cognitive decline in PDD [
      • Halliday G.M.
      • Leverenz J.B.
      • Schneider J.S.
      • Adler C.H.
      The neurobiological basis of cognitive impairment in Parkinson's disease. PubMed Commons.
      ,
      • Del Tredici K.
      • Braak H.
      Dysfunction of the locus coeruleus-norepinephrine system and related circuitry in Parkinson's disease-related dementia.
      ,
      • Irwin D.J.
      • White M.T.
      • Toledo J.B.
      • Xie S.X.
      • Robinson J.L.
      • Van Deerlin V.
      • et al.
      Neuropathologic substrates of Parkinson's disease dementia.
      ,
      • Harding A.J.
      • Halliday G.M.
      Cortical Lewy body pathology in the diagnosis of dementia.
      ]. The dopaminergic and cholinergic systems both play a key role in functional and structural remodeling of cortical circuits, and thus an imbalance within the dopamine-acetylcholine synergistic function of these pathways might lead to impaired cognitive processing [
      • Mak E.
      • Su L.
      • Williams G.B.
      • O'Brien J.T.
      Neuroimaging correlates of cognitive impairment and dementia in Parkinson's disease.
      ]. Faster rates of decline in striatal dopaminergic binding, as well as more severe striatal presynaptic dopaminergic deficiencies, particularly in the caudate has been noted in PDD [
      • O'Brien J.T.
      • Colloby S.
      • Fenwick J.
      • Williams E.D.
      • Firbank M.
      • Burn D.
      • et al.
      Dopamine transporter loss visualized with FP-CIT SPECT in the differential diagnosis of dementia with Lewy bodies.
      ,
      • Ito K.
      • Nagano-Saito A.
      • Kato T.
      • Arahata Y.
      • Nakamura A.
      • Kawasumi Y.
      • et al.
      Striatal and extrastriatal dysfunction in Parkinson's disease with dementia: a 6-[18F]fluoro-l-dopa PET study.
      ,
      • Colloby S.
      • Williams E.D.
      • Burn D.J.
      • Lloyd J.J.
      • McKeith I.G.
      • O'Brien J.T.
      Progression of dopaminergic degeneration in dementia with Lewy bodies and Parkinson's disease with and without dementia assessed using 123I-FP-CIT SPECT.
      ]. However, substantial evidence also emphasizes that dysfunction within the ascending cholinergic systems underlies dementia, particularly in PD and Dementia with Lewy Bodies (DLB) more so than Alzheimer's disease (AD) [
      • Roy R.
      • Niccolini F.
      • Pagano G.
      • Politis M.
      Cholinergic imaging in dementia spectrum disorders.
      ,
      • Bohnen N.I.
      • Albin R.L.
      • Müller M.L.T.M.
      • Petrou M.
      • Kotagal V.
      • Koeppe R.a.
      • et al.
      Frequency of cholinergic and caudate nucleus dopaminergic deficits across the predemented cognitive spectrum of Parkinson disease and evidence of interaction effects.
      ]. Extensive cholinergic neuronal loss has been noted in the nucleus basalis of Meynert in AD and to a similar or even greater extent in PD [
      • King A.
      • Liu L.
      • Chang R.C.C.
      • Pearce R.K.B.
      • Gentleman S.M.
      Nucleus basalis of Meynert revisited: anatomy, history and differential involvement in Alzheimer's and Parkinson's disease.
      ]. Thalamic cholinergic denervation has been found across PDD, DLB and to a lesser extent in PD [
      • Kotagal V.
      • Müller M.L.T.M.
      • Kaufer D.I.
      • Koeppe R.A.
      • Bohnen N.I.
      Thalamic cholinergic innervation is spared in Alzheimer disease compared to parkinsonian disorders.
      ]. Whilst individuals with AD seem to have preserved thalamic pathways [
      • Kotagal V.
      • Müller M.L.T.M.
      • Kaufer D.I.
      • Koeppe R.A.
      • Bohnen N.I.
      Thalamic cholinergic innervation is spared in Alzheimer disease compared to parkinsonian disorders.
      ], similar white matter hyperintensities in cholinergic pathways were found between AD, DLB and PDD [
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      Subcortical whiter matter hyperintensities within the cholinergic pathways of patients with dementia and parkinsonism.
      ]. Furthermore, in vivo PET studies have shown decreased acetylcholinesterase activity and nicotinic acetylcholine receptor density in both cortical and subcortical brain tissues in PDD [
      • Bohnen N.I.
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      • Lopesti B.
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      Cortical cholinergic function is more severely affected in parkinsonian dementia than in Alzheimer disease: an in vivo positron emission tomographic study.
      ,
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      • Ivanco L.S.
      • Lopesti B.
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      Cognitive correlates of cortical cholinergic denervation in Parkinson's disease and parkinsonian dementia.
      ,
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      • Weisenbach S.
      • Kalbe E.
      • Burghaus L.
      • et al.
      Dementia in Parkinson disease: functional imaging of cholinergic and dopaminergic pathways.
      ,
      • Klein J.C.
      • Eggers C.
      • Kalbe E.
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      • Vollmar S.
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      Neurotransmitter changes in dementia with Lewy bodies and Parkinson disease dementia in vivo.
      ]. Additionally, PDD have shown a greater and more widespread loss of vesicular acetylcholine transporter levels when compared to PD patients without dementia who show reduced levels only in the parietal and occipital areas rather than the entire cortex [
      • Kuhl D.
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      • Frey K.A.
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      In vivo mapping of cholinergic terminals in normal aging, Alzheimer's disease, and Parkinson's disease.
      ].
      These pathological and neurochemical abnormalities are associated with structural and functional brain changes, including atrophy and altered network connectivity (for full review please see [
      • Gratwicke J.
      • Jahanshahi M.
      • Foltynie T.
      Parkinson's disease dementia: a neural networks perspective.
      ]). A linear progression of atrophy has been suggested to occur across the cognitive stages in PD (i.e. PD-MCI to PDD), mainly affecting temporal, frontal and parietal areas [
      • Burton E.J.
      • McKeith I.G.
      • Burn D.J.
      • Williams E.D.
      • O'Brien J.T.
      Cerebral atrophy in Parkinson's disease with and without dementia: a comparison with Alzheimer's disease, dementia with Lewy bodies and controls.
      ,
      • Zarei M.
      • Ibarretxe-Bilbao N.
      • Compta Y.
      • Hough M.
      • Junque C.
      • Bargallo N.
      • et al.
      Cortical thinning is associated with disease stages and dementia in Parkinson's disease.
      ,
      • Melzer T.R.
      • Watts R.
      • MacAskill M.R.
      • Pitcher T.L.
      • Livingston L.
      • Kennan R.J.
      • et al.
      Grey matter atrophy in cognitively impaired Parkinson's disease.
      ,
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      • Doshi J.
      • Koka D.
      • Davatzikos C.
      • Siderowf A.D.
      • Duda J.E.
      • et al.
      Neurodegeneration across stages of cognitive decline in Parkinson's disease.
      ,
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      • Corcuera-Solano I.
      • Vives-Gilabert Y.
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      • García-Sánchez C.
      • Pascual-Sedano B.
      • et al.
      Pattern of regional cortical thinning associated with cognitive deterioration in Parkinson's disease.
      ,
      • Beyer M.K.
      • Janvin C.C.
      • Larsen J.P.
      • Aarsland D.
      A magnetic resonance imaging study of patients with Parkinson's disease with mild cognitive impairment and dementia using voxel-based morphometry.
      ,
      • Tam C.W.
      • Burton E.J.
      • McKeith I.G.
      • Burn D.J.
      • O'Brien J.T.
      Temporal lobe atrophy on MRI in Parkinson disease with dementia: a comparison with Alzheimer disease and dementia with Lewy bodies.
      ]. Additional subcortical areas that become atrophic as mild cognitive impairment (MCI) transitions into dementia include the thalamus [
      • Burton E.J.
      • McKeith I.G.
      • Burn D.J.
      • Williams E.D.
      • O'Brien J.T.
      Cerebral atrophy in Parkinson's disease with and without dementia: a comparison with Alzheimer's disease, dementia with Lewy bodies and controls.
      ], caudate [
      • Burton E.J.
      • McKeith I.G.
      • Burn D.J.
      • Williams E.D.
      • O'Brien J.T.
      Cerebral atrophy in Parkinson's disease with and without dementia: a comparison with Alzheimer's disease, dementia with Lewy bodies and controls.
      ,
      • Zarei M.
      • Ibarretxe-Bilbao N.
      • Compta Y.
      • Hough M.
      • Junque C.
      • Bargallo N.
      • et al.
      Cortical thinning is associated with disease stages and dementia in Parkinson's disease.
      ,
      • Melzer T.R.
      • Watts R.
      • MacAskill M.R.
      • Pitcher T.L.
      • Livingston L.
      • Kennan R.J.
      • et al.
      Grey matter atrophy in cognitively impaired Parkinson's disease.
      ,
      • Weintraub D.
      • Doshi J.
      • Koka D.
      • Davatzikos C.
      • Siderowf A.D.
      • Duda J.E.
      • et al.
      Neurodegeneration across stages of cognitive decline in Parkinson's disease.
      ,
      • Pagonabarraga J.
      • Corcuera-Solano I.
      • Vives-Gilabert Y.
      • Llebaria G.
      • García-Sánchez C.
      • Pascual-Sedano B.
      • et al.
      Pattern of regional cortical thinning associated with cognitive deterioration in Parkinson's disease.
      ,
      • Beyer M.K.
      • Janvin C.C.
      • Larsen J.P.
      • Aarsland D.
      A magnetic resonance imaging study of patients with Parkinson's disease with mild cognitive impairment and dementia using voxel-based morphometry.
      ,
      • Tam C.W.
      • Burton E.J.
      • McKeith I.G.
      • Burn D.J.
      • O'Brien J.T.
      Temporal lobe atrophy on MRI in Parkinson disease with dementia: a comparison with Alzheimer disease and dementia with Lewy bodies.
      ,
      • Beyer M.K.
      • Larsen J.P.
      • Aarsland D.
      Gray matter atrophy in Parkinson's disease with dementia and dementia with Lewy bodies.
      ,
      • Camicioli R.
      • Moore M.M.
      • Kinney A.
      • Corbridge E.
      • Glassberg K.
      • Kaye J.A.
      Parkinson's disease is associated with hippocampal atrophy.
      ,
      • Junqué C.
      • Ramírez-Ruiz B.
      • Tolosa E.
      • Summerfield C.
      • Martí M.J.
      • Pastor P.
      • et al.
      Amygdalar and hippocampal MRI volumetric reductions in Parkinson's disease with dementia.
      ], putamen [
      • Burton E.J.
      • McKeith I.G.
      • Burn D.J.
      • Williams E.D.
      • O'Brien J.T.
      Cerebral atrophy in Parkinson's disease with and without dementia: a comparison with Alzheimer's disease, dementia with Lewy bodies and controls.
      ], amygdala [
      • Zarei M.
      • Ibarretxe-Bilbao N.
      • Compta Y.
      • Hough M.
      • Junque C.
      • Bargallo N.
      • et al.
      Cortical thinning is associated with disease stages and dementia in Parkinson's disease.
      ,
      • Junqué C.
      • Ramírez-Ruiz B.
      • Tolosa E.
      • Summerfield C.
      • Martí M.J.
      • Pastor P.
      • et al.
      Amygdalar and hippocampal MRI volumetric reductions in Parkinson's disease with dementia.
      ] and hippocampus [
      • Zarei M.
      • Ibarretxe-Bilbao N.
      • Compta Y.
      • Hough M.
      • Junque C.
      • Bargallo N.
      • et al.
      Cortical thinning is associated with disease stages and dementia in Parkinson's disease.
      ,
      • Camicioli R.
      • Moore M.M.
      • Kinney A.
      • Corbridge E.
      • Glassberg K.
      • Kaye J.A.
      Parkinson's disease is associated with hippocampal atrophy.
      ,
      • Junqué C.
      • Ramírez-Ruiz B.
      • Tolosa E.
      • Summerfield C.
      • Martí M.J.
      • Pastor P.
      • et al.
      Amygdalar and hippocampal MRI volumetric reductions in Parkinson's disease with dementia.
      ]. Major white matter tracts have also been suggested to be altered in PD-MCI and PDD compared to controls, and have been associated with a decline in global cognition as well as executive impairments [
      • Hattori T.
      • Orimo S.
      • Aoki S.
      • Ito K.
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      • et al.
      Cognitive status correlates with white matter alteration in Parkinson's disease.
      ,
      • Zhang K.
      • Yu C.
      • Zhang Y.
      • Wu X.
      • Zhu C.
      • Chan P.
      • et al.
      Voxel-based analysis of diffusion tensor indices in the brain in patients with Parkinson's disease.
      ,
      • Karagulle Kendi A.T.
      • Lehericy S.
      • Luciana M.
      • Ugurbil K.
      • Tuite P.
      Altered diffusion in the frontal lobe in Parkinson disease.
      ,
      • Gattellaro G.
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      • Mariani C.
      • Carella F.
      • Osio M.
      • et al.
      White matter involvement in idiopathic Parkinson disease: a diffusion tensor imaging study.
      ,
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      • Canu E.
      • Stojković T.
      • Pievani M.
      • Tomic A.
      • Sarro L.
      • et al.
      The topography of brain damage at different stages of Parkinson's disease.
      ].
      Associations between regional activations and more specific cognitive domain deficits have also been made. For example, abnormal frontostriatal responses have been associated with deficits in executive functioning [
      • Gratwicke J.
      • Jahanshahi M.
      • Foltynie T.
      Parkinson's disease dementia: a neural networks perspective.
      ,
      • Lewis S.J.G.
      • Dove A.
      • Robbins T.W.
      • Barker R.A.
      • Owen A.M.
      Cognitive impairments in early Parkinson's disease are accompanied by reductions in activity in frontostriatal neural circuitry.
      ]. Although few studies have investigated brain metabolism in PDD, recent longitudinal research suggests that reduced glucose metabolism in occipital and posterior cingulate regions heralds those PD patients who will convert to PDD [
      • Bohnen N.I.
      • Koeppe R.a.
      • Minoshima S.
      • Giordani B.
      • Albin R.L.
      • Frey K.a.
      • et al.
      Cerebral glucose metabolic features of Parkinson disease and incident dementia: longitudinal study.
      ]. The default mode network has emerged as a key functional substrate for cognitive deficits within PD. The dorsal attention network has been found to be affected in PD-MCI and to correlate with attentional and executive deficits [
      • Baggio H.
      • Segura B.
      • Sala-Llonch R.
      • Marti M.J.
      • Valldeoriola F.
      • Compta Y.
      • et al.
      Cognitive impairment and resting-state network connectivity in Parkinson's disease.
      ]. PDD patients show further reductions in functional connectivity within the DMN beyond non-demented PD patients and controls [
      • Rektorova I.
      • Krajcovicova L.
      • Marecek R.
      • Mikl M.
      Default mode network and extrastriate visual resting state network in patients with Parkinson's disease dementia.
      ], and others have shown that impaired deactivation of the default mode network can occur specifically during executive tasks in PD [
      • Krajcovicova L.
      • Mikl M.
      • Marecek R.
      • Rektorova I.
      The default mode network integrity in patients with Parkinson's disease is levodopa equivalent dose dependent.
      ,
      • Tinaz S.
      • Schendan H.E.
      • Stern C.E.
      Fronto-striatal deficit in Parkinson's disease during semantic event sequencing.
      ].

      3. Discussion: What remains unknown?

      As highlighted above, many questions regarding the pathophysiology of behavioral disturbance in PD remain unresolved. For example, questions like how does neuronal toxicity occur and why/how does it spread? More broadly, does abnormal activity within a network contribute to the transmission of pathology, exhaustion and/or plastic changes to other networks? Furthermore, disease heterogeneity exists across multiple levels and magnifies the difficulty in not only replicating findings, but also limits the generalizability for future therapies and drug trials. Many studies described above have failed to consider age of onset, disease stage, medication profile, genetic polymorphisms or clinical phenotype. A combination of these factors is likely to interact and play a significant role in the rate of progression and underlying pathology. For example, age of onset is well known to influence alpha-synuclein deposition, and yet remains a major confounder in many studies to date [
      • Halliday G.M.
      • McCann H.
      The progression of pathology in Parkinson's disease.
      ]. Furthermore, cell loss is impossible to assess if the loss doesn't leave a marker or if the loss isn't large enough to create an imaging deficit, thus suggesting that we don't yet know what we don't know. Greater precision is also needed in the classification of subgroups under study and the coexistence of the symptoms being evaluated (e.g. hallucinators, PD-MCI, PD patients with depression, anxiety, apathy, RBD, etc.). In our opinion, future research should focus on histopathological validation, longitudinal studies (in support of cross-sectional work) and multi-modal imaging techniques to promote replication of findings.
      In conclusion, many interfacing systems are affected in PD leading to a vast array of behavioral symptoms. Although the presence of alpha-synuclein, Lewy bodies and in some cases amyloid plaques and tau provide logical possibilities for producing behavioral problems in PD, the pathophysiology remains complex, and these complexities are still not adequately understood given the highly interconnected nature of the brain and the cascade of dysfunction at many levels, where localized pathology can extend to abnormalities in global network activity [
      • Caviness J.N.
      Pathophysiology of Parkinson's disease behavior - a view from the network.
      ]. To this end, a more in depth understanding of the pathological mechanisms of PD behavior is needed in order to provide insight for future treatment strategies.

      Acknowledgments

      This work was supported by funding to Forefront, a collaborative research group dedicated to the study of non-Alzheimer disease degenerative dementias, from the National Health and Medical Research Council of Australia program grant (#1037746 and #1095127). We would also like to acknowledge Parkinson Canada for their funding support.

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