Regional Alpha-Synuclein Aggregation, Dopaminergic Dysregulation, and the Development of Drug-Related Visual Hallucinations in Parkinson’s Disease

A bout one-third of Parkinson’s disease patients develop visual hallucinations and other psychotic symptoms (delusions, agitation, paranoid beliefs, confusional states and delirium), often thought to be treatment-related. 1 , 2 Visual hallucinations are more frequent in elderly Parkinson’s disease patients and in those with cognitive impairment. 3 In such cases, dopamine agonists and anticholinergic drugs are usually withdrawn, and the dose of L -dopa reduced, significantly limiting motor performance. Atypical neuroleptic agents such as clozapine, quetiapine and olanzapine 4 , 5 help to control such manifestations but not sufficiently to permit optimal treatment of motor symptoms. Visual hallucinations also have a major impact on the natural history and prognosis of Parkinson’s disease and have been identified as one of the cardinal risk factors for nursing home placement and increased mortality. 6 An overview of the major differences in the characteristics of hallucinations between Parkinson’s disease and schizophrenia is provided in Table 1 . On the other hand, the psychotic symptoms that occur in the context of an organic-systematic disease (i.e., infections) and in the absence of an underlying neurochemical imbalance can be generally attributed to a global central nervous system impairment associated with a metabolic encephalopathy. 7

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Although the clinical and epidemiological features of visual hallucinations in Parkinson’s disease have been extensively reviewed, 2 their etiopathogenesis remains open to debate. There is a critical gap in the knowledge base that centers on neurodegenerative alterations and neurotransmitter system deficiencies in Parkinson’s disease patients with visual hallucinations and other psychotic symptoms. This seriously limits therapeutic efficacy and may prevent the successful development of novel interventions like neurogenic stem cells grafting 8 , 9 and gene therapy using viral vector-mediated delivery of glial cell-derived neurotrophic factor in the substantia nigra and the striatum. 10 – 12

In this review the current knowledge on the potential impact of the regional neurodegenerative process of Parkinson’s disease in the development of visual hallucinations as well as the possible role of the dopamine transporter and dopamine receptors is summarized.

The Role of Alpha-Synuclein

Alpha-synuclein is a marker of neurodegeneration in Parkinson’s disease. 13 It is a major constituent of Lewy bodies and Lewy neurites, 14 – 16 which have been found in higher densities in temporolimbic areas in patients with visual hallucinations. 17 Increased alpha-synuclein burden in temporolimbic and mesocorticolimbic areas may therefore be one of the key factors related to the development of visual hallucinations and other psychotic symptoms in Parkinson’s disease patients.

The synucleins are a family of soluble presynaptic proteins that are abundant in neurons and include alpha-synuclein, beta-synuclein and gamma-synuclein. 18 , 19 The function of alpha-synuclein, not yet fully clear, appears to involve maintenance and transport of synaptic vesicles 20 , 21 and participation in neuronal function through multiple interactions with other proteins and through its involvement in lipid transport and membrane biogenesis. 22 Mutations in the alpha-synuclein gene leading to abnormal protein folding 23 , 24 or protein overexpression 25 have been shown to cause familial Parkinson’s disease. Pathological inclusions of alpha-synuclein have been reproduced in several animal models. 26 – 28 One example is in the drosophila melanogaster, where alpha-synuclein overexpression results in degeneration of dopaminergic neurons and motor deficits. 27 Therefore, several lines of evidence strongly support that altered alpha-synuclein function is related or can trigger the degeneration of dopaminergic neurons.

Another function of the protein alpha-synuclein is the modulation of dopamine transporter, thus maintaining the synaptic buffering of dopamine. Dopamine transporter acts to terminate dopaminergic neurotransmission by reaccumulation of dopamine into presynaptic neurons. It thus plays a central role in the spatial and temporal buffering of released dopamine and key roles in its recycling. 29 Disruption of this function of alpha-synuclein may result in abnormal intracellular and extracellular dopamine content, which may represent an alternative route leading to degeneration of the presynaptic dopaminergic nerve terminals. 13

The substantia nigra is among the predilection sites of the Parkinson’s disease-related Lewy bodies and Lewy neurites. These inclusion bodies, together with the subsequent loss of its neuromelanin-containing dopaminergic projection neurons, constitute the main pathological features of the disorder. 30 Although the substantia nigra is an important focal point of the pathology, the underlying process is by no means confined to this midbrain nuclear complex. A variety of extranigral regions, especially those assigned to the limbic system (including the amygdala), are among the hardest hit targets of the Parkinson’s disease-related lesions. 31 – 33 In a clinicopathologic study 17 comparing patients with dementia with Lewy bodies and Parkinson’s disease with and without dementia, a striking association between the distribution of temporal lobe Lewy bodies and well-formed visual hallucinations was reported. Patients with well-formed visual hallucinations had high densities of Lewy bodies in the amygdala and parahippocampus, with early hallucinations relating to higher densities in parahippocampal and inferior temporal cortices. The results of this study relate the distribution of temporal lobe Lewy bodies (and therefore indirectly the alpha-synuclein burden) to the presence of visual hallucinations. Higher average Lewy bodies densities have been previously observed in paralimbic cortices in patients with visual hallucinations compared with those without. 34

The Role of the Ventral Tegmental Area, the Nucleus Accumbens and the Amygdala

The pathological hallmark of Parkinson’s disease is the degeneration of dopamine neurons of the ventral mesencephalon. This neurodegenerative process is selective, affecting specific neuronal subpopulations, whereas other neuronal groups are relatively spared. 35 , 36 In general, the mesotelencephalic dopaminergic system may be divided into two major parts: the dorsal, nigrostriatal, part, which is mainly responsible for motor programming; and the ventral part, which extends from the ventral tegmental area through the ventral striatum either to the limbic (mesolimbic system) or frontal cortex (mesocortical system), and which is implicated in thought and behavioral programming. While disruption of the dorsal (nigrostriatal) dopamine pathway leads to the motor symptoms commonly seen in Parkinson’s disease, disruption of the ventral mesocorticolimbic dopamine system may be the key factor in the development of psychotic symptoms (mainly visual hallucinations). A schematic representation of this division is provided in Figure 1 .

Ventral Tegmental Area

The ventral tegmental area is a region in the mesencephalon which is dorsomedial to the substantia nigra and ventral to the red nucleus. The mesocortical and mesolimbic dopaminergic systems originate here, including important projections to the ventral striatum and the nucleus accumbens. Dysfunction of the neurons with their cell bodies in the ventral tegmental area and projections to the prefrontal cortex and limbic system have been implicated in psychotic states. 37 In Parkinson’s disease, ventral tegmental area neurons are depleted from 36% to 55% of control values. 38

The midbrain dopamine system can be divided into two groups of cells based on chemical characteristics and connectivity. The dorsal tier neurons, which include the dorsal substantia nigra pars compacta and the ventral tegmental area, are calbindin-positive, and project to the nucleus accumbens. The ventral tier neurons are calbindin-negative and project to the sensorimotor striatum. 39 In general, neurons of the ventral tier of the substantia nigra pars compacta are more vulnerable in Parkinson’s disease patients, followed by those of the dorsal tier, with relative sparing of the medial substantia nigra and pars lateralis. 40 In Parkinson’s disease patients with visual hallucinations and other psychotic symptoms, dorsal tier areas and especially the ventral tegmental area may be more affected when compared to patients without. The ventral tegmental area may act in the development of psychotic symptoms in a way similar to the substantia nigra in the development of motor symptoms.

Nucleus Accumbens

The concept of the ventral striatum was originally developed in the classic paper by Heimer and Wilson 41 that describes the relationship between the nucleus accumbens and the olfactory tubercle in rats. The authors showed that striatal-like and pallidal-like elements of the olfactory tubercle constitute a ventral continuation of the striatum, and, therefore, together with the nucleus accumbens, these structures should be referred to as the ventral striatum. Since then, the ventral striatum and its connections have been at the center of the reward circuit, and, as such, have been a research focus of the neurobiological mechanisms underlying drug addiction, and mental and thought disorders. 42

The nucleus accumbens is that part of the ventral striatum that has long been associated with the limbic system or with that group of structures thought to mediate motivational and emotional responses to environmental stimuli. This association is based on, among other things, its afferent connections from the amygdala and prefrontal cortical areas (both involved in mechanisms of reward and positive reinforcement). 39 The nucleus accumbens and its related circuits are also implicated in thought, attention and cognition. Dysfunction in the information processing in the nucleus accumbens may lead to the development of visual hallucinations. 43 , 44 Nucleus accumbens receives afferent input from brain regions presumably involved in the pathogenesis of schizophrenia, including the ventral tegmental area, prefrontal cortex, the hippocampus and the amygdala. 45 It sends projections to the ventral pallidum, which in turn sends a major projection to the mediodorsal nucleus of the thalamus, which is interconnected with the prefrontal cortex and regulates its activity. 46 , 47 There is evidence that both hippocampal and amygdalar input to the nucleus accumbens can affect its capability of processing and transferring information from prefrontal afferents to the ventral pallidum and the thalamocortical system. 48 In the normal functioning brain, the balance of inputs from cortical and mediotemporal structures to the nucleus accumbens is used to prepare, initiate and prevent selected thoughts and behaviors. 49 As such, the nucleus accumbens acts as a subcortical integrative hub, connecting forebrain and limbic structures and controlling the flow and processing of information. 50 Structural (neurodegenerative) damage and neurochemical imbalance in this sensitive striatal area may precipitate the genesis of visual hallucinations and possibly other psychotic phenomena seen in Parkinson’s disease. In summary, the involvement of the nucleus accumbens in the generation of visual hallucinations and other psychotic symptoms may be as important as the function of the internal part of the globus pallidus in the generation of motor symptoms.

Amygdala

The amygdala has long been suspected to contribute to psychotic symptoms because its stimulation (often by temporal lobe epilepsy) could provoke positive symptoms like hallucinations. 51 , 52 A clinicopathological analysis of demented patients with dementia with Lewy bodies revealed high amygdala Lewy bodies densities in patients who had well-formed visual hallucinations during life. 17 In another study of nondemented Parkinson’s disease patients, 53 a similar correlation was observed, with the subregion involved localized to the basolateral nucleus. Selective basolateral neuronal loss has been also reported in temporal lobe epilepsy, 54 where memory-like hallucinations and feelings of deja-vu were evoked from amygdala stimulation in 73% of cases. 55

Recent experiments have implicated the amygdala in visual dysfunction by showing its important role in the integration of parallel visual systems. 56 , 57 The amygdala appears to be the final processing center for the ventral stream of the cortical visual system subserving conscious visual identification and discrimination 58 and the extrageniculostriate (colliculo-thalamo-amygdala) visual system, which is related with automatic, nonconscious emotional visual processing (blindsight). 58 Dopamine receptor activation in the basolateral nucleus removes prefrontal cortex-induced suppression of neuronal output and enhances activity driven by sensory inputs. 59 The increased alpha-synuclein burden in the basolateral amygdaloid nucleus is likely to disrupt the ability of the amygdala to integrate coordinated behavioral responses between the two visual systems. This, in association with dopamine replacement therapies, may precipitate the visual hallucinations experienced by the patients with Parkinson’s disease.

Dopaminergic System Involvement in the Development of Visual Hallucinations in Parkinson’s Disease

Catecholamines of the midbrain, especially dopamine, are known to be involved in the pathophysiology of psychiatric disease and especially in schizophrenia. 60 Furthermore, classical neuroleptic drugs used in the treatment of schizophrenia act primarily on receptors for dopamine. 61 Visual hallucinations not only are drug-related in the majority of cases, but lowering or withdrawal of dopamine stimulation usually leads to improvement of symptoms. If the above adjustments fail to eliminate or sufficiently alleviate visual hallucinations, a trial of antipsychotics should be considered. 62 , 63 Attention must be paid to avoid exacerbation of parkinsonism, since all of the antipsychotics have the potential capacity to block striatal dopamine D2 receptors. The best choices at present are atypical antipsychotics, clozapine and quetiapine, which can reduce visual hallucinations and other psychotic symptoms without worsening parkinsonism. 64

Dopamine Transporter

Dopamine transporter is an important molecule in the pathogenesis of motor and nonmotor symptoms in Parkinson’s disease. 65 Human dopamine transporter is a 620 amino acid, single-subunit membrane protein with 12 membrane spanning regions and a large second extracellular loop. 66 It is most selectively expressed by the dopamine neurons most damaged in Parkinson’s disease. The activity and levels of dopamine transporter expression provide vital determinants of dopamine function. Dopamine transporter acts to terminate dopamine neurotransmission by reaccumulation of dopamine into presynaptic neurons. It thus plays a central role in its recycling and its temporospatial buffering. 29 Reuptake activity has a profound effect on dopaminergic neurotransmission and its biochemical, physiological, and behavioral functions.

There are regional variations in the expression of dopamine transporter. Dopamine transporter is relatively low throughout the ventral striatum. This pattern is consistent with the fact that the dorsal tier dopamine neurons express relatively low levels of mRNA for the dopamine transporter compared to the “ventral tier.” 67 Animal data indicate that dopamine transporter levels are also related to chronic exposure to dopaminergic drugs that can alter, by an as yet unknown mechanism, striatal levels of dopamine transporter without any change in the number of dopamine nerve terminals. However, in such studies the direction of the change is not always consistent. 68 Striatal dopamine transporter levels following L -dopa treatment have been reported to be unchanged, 69 – 75 increased, 72 , 76 and reduced 77 in both animal and human studies.

Alterations in dopamine transporter expression may prove important for understanding the neurochemical basis for visual hallucinations and other psychotic symptoms in Parkinson’s disease. Support for the involvement of dopamine transporter is also provided by high affinity binding of psychotherapeutic drugs (mazindol, nomifensine, and tricyclic antidepressants), drugs of abuse (including cocaine, d -amphetamine, and phencyclidine), and neurotoxins such as 6-hydroxydopamine and 1-methyl-4-phenylpyridinium (the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP]) to dopamine transporter. 78

The reduction in striatal dopamine transporter probably reflects dopamine neuronal loss (presynaptic terminal loss) that contributes to some of the negative clinical outcomes in patients with Parkinson’s disease. Any loss of the ability to prevent marked changes in synaptic dopamine concentration following replacement treatment with L -dopa could increase the likelihood of developing long-term, drug-induced response fluctuations. 79 We believe that these fluctuations may be either motor (on-off phenomena and dyskinesias) or nonmotor (positive psychotic symptoms like visual hallucinations—thought fluctuations). During the initial stages of the disease, before the severe dopaminergic nerve terminal damage, the coordinated regulation of dopamine transporter and alpha-synuclein maintains some synaptic buffering of dopamine. 13 With disease progression the modulatory action of alpha-synuclein is partially lost and there is further reduction in presynaptic dopaminergic terminals, allowing the genesis of mild wearing-off symptoms. With severe neuronal and dopamine transporter loss the synaptic buffering ability is also lost contributing to visual hallucinations and other psychotic symptoms development. However, one should avoid simplistic explanations since the pathogenesis of these symptoms is far more complex and multifactorial (a review of the proposed involvement of the dopaminergic system is provided in Figure 2 ).

Dopamine Receptors

dopamine plays an important, and often necessary, role in a wide variety of behaviors and functions, ranging from movement to thought and emotion, sensitization to addiction, and development of plasticity. In part, this diversity reflects the organization of the multiple types of dopamine receptors. As all antipsychotics and antiparkinsonian agents act predominantly through the D2 subfamily of receptors, it is important to understand what functions the subtypes might mediate. This is particularly true since these receptor subtypes are differentially expressed in regions of the human brain, providing a rationale for how they could mediate different actions of dopamine. 80

An understanding of how dopaminergic receptors act in the striatum requires familiarity with its basic organization. As initially postulated, 41 it has now been convincingly demonstrated that there are parallel efferent circuits originating from the dorsal and ventral striatum with analogous “direct” and “indirect” pathways. 81 “Direct” pathway neurons project to the internal segment of the globus pallidus and substantia nigra pars reticulata, and express substance P and preprotachykinin mRNA. “Indirect” pathway neurons project to the external segment of the globus pallidus and subthalamic nucleus and express enkephalin (preproenkephalin mRNA). “Direct” (striatonigral) and “indirect” (striatopallidal) output neurons preferentially express D1 and D2 receptors, respectively. The influences of the direct and indirect pathways are considered to be opposing, and dopamine tonically modulates these two pathways via inhibition of the indirect pathway through the D2 receptor and via excitation of the direct pathway through the D1 receptor. Similar “direct” and “indirect” pathways that might be involved in visual hallucinations and other psychotic symptoms in Parkinson’s disease have been identified in the limbic striatum. Neurons within the nucleus accumbens project primarily to the ventral pallidum, with the core of the nucleus accumbens projecting to the lateral ventral pallidum, which sends projections to the subthalamic nucleus and substantia nigra pars reticulata. The shell of the nucleus accumbens projects to the medial ventral pallidum, which provides efferents to the mediodorsal thalamus. 82 As cells in the shell of the nucleus accumbens coexpress D ¹ mRNA and Sub P and the cells in the core of the nucleus accumbens preferentially express D2 mRNA and ENK, 83 they are presumed to modulate direct and indirect ventral striato-pallidal-thalamo pathways, respectively. These “direct” and “indirect” limbic striatal pathways may be related to the development of visual hallucinations and other psychotic symptoms in Parkinson’s disease in a way similar to the involvement of the motor striatal “direct” and “indirect” pathways.

There are several studies (in both Parkinson’s disease animal models and patients) on the involvement of the striatal dopaminergic receptors (dorsal and ventral parts) in Parkinson’s disease. A recent report in nonhuman primates (MPTP treated monkeys) demonstrated up-regulation of both D1 and D2 dopamine receptors in the denervated striatum. 84 Consistent with these measurements of dopamine receptor protein levels, others have reported increased dopamine receptor binding in MPTP-treated monkeys and cats, as well as in Parkinson’s disease patients. 85 – 90 Striatal D2 binding has been shown to be increased in unilaterally lesioned monkeys on the denervated as compared to the control side. 91 , 92 All of these studies demonstrate that nigrostriatal dopamine denervation caused either by the neurodegenerative process of Parkinson’s disease or by selective lesioning causes a significant compensatory up-regulation of striatal dopamine receptors (denervation supersensitivity). When supersensitive dopamine receptors are stimulated by dopaminergic supplementation therapy (standard treatment in Parkinson’s disease), the delicate neurochemical balance of the nucleus accumbens may be disrupted leading to psychotic symptom development ( Figure 2 ).

Summary

The dopaminergic system seems to have a key role in the development of visual hallucinations in Parkinson’s disease via several mechanisms; however, their exact etiology remains unknown. The major event proposed in this review is the dysregulation of the ventral dopaminergic pathway that occurs with disease progression and is accompanied by regional increase of alpha-synuclein burden. Replacement therapy ( L -dopa) stimulating the supersensitive dopamine receptors of the dysregulated ventral pathway may allow the genesis of visual hallucinations. The schematic overview for the proposed role of the dopaminergic system in the development of visual hallucinations in Parkinson’s disease is shown in Figure 2 .