Review articleGenetic substrates of psychosis in patients with Parkinson's disease: A critical review
Introduction
Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder. Bradykinesia, rigidity, tremor at rest and postural instability are the important motor features of PD [1]. In addition to the motor features, patients with PD may develop various non-motor symptoms (NMS) such as psychosis, depression, cognitive decline, autonomic dysfunctions and sleep disturbances [2], [3]. Psychosis is one of the common and debilitating NMS of PD, which commonly manifests as minor hallucinations (presence hallucination and passage hallucination) and formed visual hallucinations (VH). Though delusions and hallucinations of modalities other than visual such as auditory, tactile and gustatory are also observed in PD, they are uncommon and usually coexist with formed VH [4], [5]. Dopaminergic therapy, long duration of PD, older age of the patients and sleep disturbances have been described as risk factors for emergence of VH in PD [6], [7]. Though dopaminergic therapy is a well-known risk factor for emergence of psychosis, patients with PD who received high dose intravenous levodopa in an experimental study did not experience any VH [8]. Further, not all patients on long-term dopaminergic therapy develop psychotic symptoms, inviting the speculation that there may be other risk factors predisposing individuals with PD to develop psychosis. Hence many studies based on neuroimaging and genetic polymorphisms have been conducted to explore the risk factors other than dopaminergic medications for development of psychosis in PD. Presence of psychosis has been reported to be an independent risk factor for development of dementia, increased nursing home placements [9] and mortality [10] in patients with PD. This underscores the importance of early identification of PD patients who are at risk of developing psychosis in order to formulate therapies to prevent or to treat psychotic symptoms in PD. Genetic biomarkers for psychosis in PD are of immense importance compared to the neuroimaging and molecular biomarkers because the genetic elements are fairly stable throughout the life of a patient and are not usually affected by the duration or severity of the disease. Identification of the association of any particular genotype or genetic mutation with psychosis in PD may open up new preventive and therapeutic avenues. The purpose of this review is to analyze the previous studies based on genetic polymorphisms in PD patients with psychosis, which may provide a clue towards identifying the PD patients susceptible to psychosis during the course of their illness.
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Search strategies and selection criteria
The relevant criteria of the preferred reporting items for systematic reviews and meta-analyses (PRISMA) were taken into consideration for this review. We searched the literature in PubMed and PsycINFO database till August 2015 for articles on genetic polymorphism in PD patients with psychotic symptoms. A broad search strategy was applied by using a number of terms and combinations, details of which are given in Table 1. A large number of studies were excluded after screening the titles,
Conclusions
Polymorphism of multiple genes has been studied to explore possible associations with psychotic symptoms in PD. Most studies were on the ApoE polymorphism followed by studies on polymorphisms of CCK gene. Of all the polymorphisms reviewed, the − 45C > T polymorphism of CCK gene was found to have association with hallucinations in 75% of the studies (3 out of 4). This makes − 45C > T polymorphism a potential target for future studies. Further confirmation of the association of − 45C > T polymorphism with
Financial disclosure/Conflict of interest
None of the authors have any financial disclosure to make or have any conflict of interest.
Source of funding
Nil.
Acknowledgement
Nil.
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2017, Asian Journal of PsychiatryCitation Excerpt :Older age of the patients, greater severity of motor symptoms, higher stage of PD, long-term treatment with dopaminergic medications, and disturbances of sleep and cognition have been described as risk factors for emergence of psychosis in PD (Fénelon et al., 2000; Lenka et al., 2016c). Although several studies based on advanced neuroimaging (Lenka et al., 2015), neuropsychological evaluations (Lenka et al., 2016b), and genetic polymorphisms (Lenka et al., 2016a) have explored the underpinnings of psychosis in PD, the exact pathophysiology has not been fully understood. Although the mechanism of VH in PD remains controversial, majority of the studies posit the possible existence of an aberrant top-to-bottom visual processing unit dominating over the bottom-to-top processing of visual information (Bar, 2003; Bar et al., 2006).
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2017, Journal of the Neurological SciencesCitation Excerpt :APOE is the most commonly studied gene in PD patients with psychosis. However, only one out seven such studies has reported significant association of the APO ε4 allele with VH [65,66]. So far, the studies on polymorphisms in the CCK gene have yielded relatively consistent results as three out of four studies have reported significant association of CCK − 45C > T polymorphism with the presence of hallucinations [67–70].
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2017, Parkinsonism and Related DisordersCitation Excerpt :Hence early identification of patients who are prone to have psychosis is of paramount importance. Several studies have been conducted to explore the neural and genetic correlates of psychosis in PD [9–11], however the findings have not been consistent. Studies based on neuroimaging, histopathology and neuropsychological evaluations have speculated a strong nexus of psychosis with cognitive impairment and rapid eye movement sleep behavior disorder (RBD) in patients with PD [12].
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2017, International Review of NeurobiologyCitation Excerpt :The combined National Institute of Neurological Disorders and Stroke (NIDHS) and National Institute of Mental Health (NIMH) work group suggests that PD psychosis consists of a continuum of minor illusions, hallucinations with insight, hallucinations without insights, and delusions that progress throughout the disease course. There were recent reviews of the genetics of psychotic symptoms in PD and PD psychosis (Ffytche et al., 2017; Lenka, Arumugham, Christopher, & Pal, 2016). There are consistent reports that demonstrate the association of GBA mutations and PD psychosis (Li, Sekine, et al., 2014; Neumann et al., 2009; Oeda et al., 2015).