Research on the Premotor Symptoms of Parkinson's Disease
Research on the Premotor Symptoms of Parkinson's Disease
An inherent implication of research on premotor symptoms is that it may eventually lead to a better understanding of PD etiology (Hawkes et al. 2007, 2009). The concept that premotor symptoms represent intermediate phenotypes prior to overt PD may offer us a vehicle to understand the roles of genetics and environment in the early stages of PD development. For example, neurotoxicants or viruses may enter the body via the nasal cavity or the digestive tract (Hawkes et al. 2007, 2009), and, in susceptible individuals, may initiate Lewy pathology in the olfactory bulb or the enteric nerves (Doty 2008; Hawkes et al. 2007, 2009; Reichmann 2011); over time, this may lead to premotor symptoms such as hyposmia or constipation and may eventually progress to PD. It is therefore important to identify environmental and genetic factors associated with the presence of multiple premotor symptoms and, more importantly, to identify factors that may prevent the progression of premotor symptoms to clinical PD. This concept is illustrated in Figure 2.
(Enlarge Image)
Figure 2.
A hypothesis on risk factors, premotor symptoms, and PD. Environmental or genetic factors may initiate neurodegeneration through mechanisms such as neuroinflammation; in susceptible individuals, this may first lead to premotor symptoms years before PD clinical onset; if this neurodegeneration continues without effective intervention, premotor symptoms may eventually progress into overt PD; however, with interventions such as coffee drinking, this premotor progression may be halted before it becomes irreversible.
To the best of our knowledge, no epidemiological study has examined common etiological factors for the presence of multiple non-motor symptoms. Preliminary data are available only on risk factors for individual symptoms.Postuma et al. (2012c) recently published the first report on environmental risk factors for RBD. In this multicenter study of 347 cases and 347 controls, RBD was positively associated with pesticide exposure and head injury. However, unlike PD, RBD was more common among smokers and was not related to caffeine intake. More studies have examined risk factors associated with hyposmia. All studies found that the risk of hyposmia increases with age and is higher in men than in women (Brämerson et al. 2004; Schubert et al. 2011, 2012; Siderowf et al. 2007, 2012; Vennemann et al. 2008). Data on smoking or coffee drinking and hyposmia are, however, preliminary and inconsistent (Brämerson et al. 2004; Schubert et al. 2011, 2012; Siderowf et al. 2007, 2012; Vennemann et al. 2008), although current smoking is associated with a higher risk of hyposmia in some studies (Schubert et al. 2012; Vennemann et al. 2008). In adults, the prevalence of constipation is higher in women and increases modestly with age (McCrea et al. 2009; Suares and Ford 2011). Other suspected risk factors for constipation include inadequate fluid or dietary fiber intake, less physical activity, concurrent use of certain medications, levels of thyroid hormone and progesterone, and a wide range of medical conditions including neurodegenerative diseases (Leung 2007; Leung et al. 2011). Therefore, risk factors for individual non-motor symptoms are diverse, and PD-related pathology is probably only a small contributor to the prevalence of each of these symptoms. Combining multiple premotor symptoms may rule out some diverse pathologies unrelated to PD. Further, PD is likely to be phenotypically and etiologically heterogeneous (van Rooden et al. 2009, 2011); and careful phenotyping of various PD motor and non-motor symptoms may help us understand the interrelationship among risk factors, premotor symptoms, and neurodegeneration.
Although human observational studies are essential to define premotor symptoms and their relationship to PD development, experimental studies are needed to understand the underlying biology and to examine novel etiological hypotheses. For example, could the gastrointestinal tract or the olfactory bulb be the sites of initial exposure to a pathogenic environmental agent (Reichmann 2011)? Does pathology progress anatomically, as the Braak hypothesis predicts (Pan-Montojo et al. 2012)? Does the selectivity and order of neurodegeneration in PD reflect differential sensitivity to environmental agents or some other mechanism of progression such as prion-like spreading (Dunning et al. 2012)? Experimental research that models prodromal PD may help answer these questions.
Animal models based on toxicants [e.g., 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine(MPTP), 6-hydroxydopamine (6-OHDA), paraquat, rotenone] and those based on genes [e.g., SNCA (α-synuclein), LRRK2, PINK1 (PTEN-induced putative kinase 1), PARK2 (parkin)] have been used for PD research (Bezard et al. 2012; Blesa et al. 2012). These models were developed to mimic features of late-stage PD such as dopaminergic neuron loss and motor dysfunction, or to recapitulate particular pathogenic processes such as neuroinflammation. The extent to which current models replicate the non-motor features of PD is incompletely known at present, although recent work has revealed some intriguing results suggesting abnormalities analogous to non-motor features of PD (Jellinger 2011; McDowell and Chesselet 2012; Smith et al. 2012).
Central to this work is the availability of validated methods to evaluate olfaction, gastrointestinal function, sleep disturbances, or depression/anxiety in experimental animals. The technical difficulties of reliably determining the presence or absence of these non-motor features in experimental animals are not trivial. Furthermore, the mechanistic relationship between abnormalities observed in the commonly used assays in experimental animals and the analogous symptoms in human patients is uncertain, especially for complex behavioral traits such as depression and anxiety. Nonetheless, ways to evaluate these non-motor symptoms have been reported in mice, rats, primates, and zebrafish. Each of these animals shows phylogenetic conservation of neuroanatomical structures involved in early Braak stages of PD pathology, suggesting that they might be employed as models to study premotor PD.
So far, a number of animal models of PD have shown either non-motor functional abnormalities or pathology outside the substantia nigra. Olfactory function has been shown to be abnormal in MPTP-treated rodents (Schintu et al. 2009), transgenic mice expressing α-synuclein under a neuronal regulatory element derived from the Thy1 gene (Thy1-α Syn) (Fleming et al. 2008), and mice expressing reduced levels of the vesicular monoamine transporter (VMAT) (Taylor et al. 2009). Sleep and circadian rhythm are known to be disrupted in MPTP-treated rodents (Laloux et al. 2008), rotenone-treated rats (García-García et al. 2005), and Thy1-αSyn mice and VMAT2-deficient mice (Taylor et al. 2009). Gastrointestinal function has been shown to be abnormal in MPTP-treated mice (Anderson et al. 2007), rotenone-treated rats (Drolet et al. 2009), Thy1-αSyn mice (Wang et al. 2008, 2012), SNCA PAC mice (which expresss mutant human α-synuclein from a P1 artificial chromosome containing its endogenous regulatory elements) (Kuo et al. 2010), and VMAT2-deficient mice (Taylor et al. 2009). These findings are of interest because they demonstrate that toxicant exposures and genetic manipulations used to induce motor signs of PD can also induce non-motor features. This suggests that at least some of the neuronal populations underlying non-motor symptoms share susceptibility with dopamine neurons to agents implicated in motor PD pathogenesis. This is consistent with a model in which common etiological mechanisms could underlie both motor and non-motor components of the disease.
Interestingly, a few of the models have shown ordered progression from non-motor to motor symptoms. Thy1-αSyn transgenic mice showed α-synuclein inclusions in the olfactory bulb and deficits in olfactory function on multiple tests by 3 months of age (Fleming et al. 2008). By this time point, animals also showed progressively worsening sleep abnormalities (Kudo et al. 2011) and progressive reduction in stool frequency (Wang et al. 2012). These changes preceded loss of striatal dopamine, which did not occur until 14 months of age (Lam et al. 2011). Similarly, VMAT2-deficient mice demonstrated progressive non-motor symptoms prior to the onset of motor deficits (Taylor et al. 2009). Gastrointestinal dysfunction was seen at 2 months of age, olfactory defects by 5 months, and anxiety-like behavior at 6 months. L-dihydroxyphenylalanine (L-DOPA)–responsive hypokinesia and loss of striatal tyrosine hydroxylase terminals were present by 18 months of age, and loss of nigral dopamine neurons worsened between 18 and 24 months (Caudle et al. 2007). Data from both models imply that a systemic abnormality affecting all cells can result in specific abnormalities of neuronal populations implicated in non-motor and motor PD with replication of some of the temporal course.
These data do not yet allow us to distinguish between a model for pathogenic progression in which the temporal course of the disease is dictated by the differential vulnerability of various neuronal groups to a systemic abnormality and an alternative model in which pathology spreads anatomically from one site of the nervous system to another to produce progressive symptoms. Much recent attention has been given to the idea that α-synuclein has prion-like properties and that α-synucleinopathy can spread from a site of initial pathology to other regions of the central nervous system (CNS) by axonal transport and cell-to-cell spread (Luk et al. 2012). In this regard, it is noteworthy that the pathology in both Thy1-αSyn mice (Fleming et al. 2004) and VMAT2-deficient mice (Taylor et al. 2009) is dependent on the presence of α-synuclein. However, several alternative explanations for the progression of disease are equally consistent with the available data and further studies will be necessary to determine whether progression can be arrested by interventions that prevent the transport or transmission of pathological α-synuclein species, or whether additional cellular factors dictate the differential vulnerability of neuronal groups involved in non-motor symptoms.
The hypothesis that an environmental agent could provoke pathology at an anatomical site of entry that then progresses to involve other structures, culminating in degeneration of the substantia nigra, has received some preliminary experimental support. For example, Jang et al. (2009) reported that, in mice, intranasally injected H5N1 influenza virus travelled from the enteric nervous system (ENS) into the CNS and eventually caused degeneration of dopaminergic neurons. Further, this sequence was accompanied by chronic neuroinflammation with microglial activation and elevated expression of cytokines and other proinflammatory biomarkers (Jang et al. 2012). These findings imply that initiating pathogenic events can provoke distinct secondary mechanisms underlying disease progression, with the important implication that environmental agents that trigger early events in PD pathogenesis may no longer be present at the end stage of the disease, when tissue samples are generally available for analysis.
The gastrointestinal tract is potentially an important site for exposure to environmental agents, and the suggestion that α-synuclein pathology in the ENS may be one of the first abnormalities in PD patients has promoted interest in the possibility of modeling pathology in the ENS and its subsequent progression to the CNS. Transgenic mice expressing human α-synuclein under its own regulatory elements showed prominent ENS pathology, but no progression to other features of PD (Kuo et al. 2010), suggesting that a second event was necessary to promote disease progression. Recent reports showed that intragastric rotenone caused α-synuclein aggregation in mice, following a staged pattern that was consistent with the Braak hypothesis (Pan-Montojo and Funk 2010; Pan-Montojo et al. 2010), and resection of the autonomic nerves prevented this progression (Pan-Montojo et al. 2012). These interesting observations are yet to be replicated by other laboratories, and their interpretation consequently remains speculative. However, the local microenvironment of the gastrointestinal tract remains a potentially significant factor in dictating initiating pathogenic events, and is worthy of further investigation. This might also encompass evaluation of the role of the gut microbiome, which could be experimentally manipulated in animal models to determine whether alterations can initiate PD pathology or modulate the time course of onset of pathology and progression. Although few empirical data exist regarding the role of the microbiome in PD, the microbiome influences the immune system, gastrointestinal mobility, and the metabolism of nutrients and other exogenous chemicals (Grenham et al. 2011), all of which may potentially contribute to the development of PD. Similarly, experimental animals could be exposed to toxicants through the gastrointestinal tract to evaluate whether etiologically implicated exogenous agents can provoke the earliest pathological changes of PD or modulate their appearance in experimental models. These studies could provide valuable mechanistic insights and generate further hypotheses to be addressed in human studies.
Finally, although this review focuses on PD, research on premotor symptoms may have broader implications because many of these symptoms have been linked to other neurological diseases. For example, hyposmia is associated with higher risk of cognitive decline and Alzheimer's disease (Wilson et al. 2007, 2009), and RBD precedes Lewy body dementia and multiple system atrophy (Schenck et al. 2013). Further, olfactory dysfunction has been documented in schizophrenic patients and individuals at high risk for schizophrenia (Moberg et al. 2013). Therefore research on premotor symptoms may eventually provide novel insights into the natural history and etiology of neurodegeneration and related conditions in addition to PD, and into the complex interrelationships among these conditions.
Implications for Parkinson's Etiology and Experimental Research
An inherent implication of research on premotor symptoms is that it may eventually lead to a better understanding of PD etiology (Hawkes et al. 2007, 2009). The concept that premotor symptoms represent intermediate phenotypes prior to overt PD may offer us a vehicle to understand the roles of genetics and environment in the early stages of PD development. For example, neurotoxicants or viruses may enter the body via the nasal cavity or the digestive tract (Hawkes et al. 2007, 2009), and, in susceptible individuals, may initiate Lewy pathology in the olfactory bulb or the enteric nerves (Doty 2008; Hawkes et al. 2007, 2009; Reichmann 2011); over time, this may lead to premotor symptoms such as hyposmia or constipation and may eventually progress to PD. It is therefore important to identify environmental and genetic factors associated with the presence of multiple premotor symptoms and, more importantly, to identify factors that may prevent the progression of premotor symptoms to clinical PD. This concept is illustrated in Figure 2.
(Enlarge Image)
Figure 2.
A hypothesis on risk factors, premotor symptoms, and PD. Environmental or genetic factors may initiate neurodegeneration through mechanisms such as neuroinflammation; in susceptible individuals, this may first lead to premotor symptoms years before PD clinical onset; if this neurodegeneration continues without effective intervention, premotor symptoms may eventually progress into overt PD; however, with interventions such as coffee drinking, this premotor progression may be halted before it becomes irreversible.
To the best of our knowledge, no epidemiological study has examined common etiological factors for the presence of multiple non-motor symptoms. Preliminary data are available only on risk factors for individual symptoms.Postuma et al. (2012c) recently published the first report on environmental risk factors for RBD. In this multicenter study of 347 cases and 347 controls, RBD was positively associated with pesticide exposure and head injury. However, unlike PD, RBD was more common among smokers and was not related to caffeine intake. More studies have examined risk factors associated with hyposmia. All studies found that the risk of hyposmia increases with age and is higher in men than in women (Brämerson et al. 2004; Schubert et al. 2011, 2012; Siderowf et al. 2007, 2012; Vennemann et al. 2008). Data on smoking or coffee drinking and hyposmia are, however, preliminary and inconsistent (Brämerson et al. 2004; Schubert et al. 2011, 2012; Siderowf et al. 2007, 2012; Vennemann et al. 2008), although current smoking is associated with a higher risk of hyposmia in some studies (Schubert et al. 2012; Vennemann et al. 2008). In adults, the prevalence of constipation is higher in women and increases modestly with age (McCrea et al. 2009; Suares and Ford 2011). Other suspected risk factors for constipation include inadequate fluid or dietary fiber intake, less physical activity, concurrent use of certain medications, levels of thyroid hormone and progesterone, and a wide range of medical conditions including neurodegenerative diseases (Leung 2007; Leung et al. 2011). Therefore, risk factors for individual non-motor symptoms are diverse, and PD-related pathology is probably only a small contributor to the prevalence of each of these symptoms. Combining multiple premotor symptoms may rule out some diverse pathologies unrelated to PD. Further, PD is likely to be phenotypically and etiologically heterogeneous (van Rooden et al. 2009, 2011); and careful phenotyping of various PD motor and non-motor symptoms may help us understand the interrelationship among risk factors, premotor symptoms, and neurodegeneration.
Although human observational studies are essential to define premotor symptoms and their relationship to PD development, experimental studies are needed to understand the underlying biology and to examine novel etiological hypotheses. For example, could the gastrointestinal tract or the olfactory bulb be the sites of initial exposure to a pathogenic environmental agent (Reichmann 2011)? Does pathology progress anatomically, as the Braak hypothesis predicts (Pan-Montojo et al. 2012)? Does the selectivity and order of neurodegeneration in PD reflect differential sensitivity to environmental agents or some other mechanism of progression such as prion-like spreading (Dunning et al. 2012)? Experimental research that models prodromal PD may help answer these questions.
Animal models based on toxicants [e.g., 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine(MPTP), 6-hydroxydopamine (6-OHDA), paraquat, rotenone] and those based on genes [e.g., SNCA (α-synuclein), LRRK2, PINK1 (PTEN-induced putative kinase 1), PARK2 (parkin)] have been used for PD research (Bezard et al. 2012; Blesa et al. 2012). These models were developed to mimic features of late-stage PD such as dopaminergic neuron loss and motor dysfunction, or to recapitulate particular pathogenic processes such as neuroinflammation. The extent to which current models replicate the non-motor features of PD is incompletely known at present, although recent work has revealed some intriguing results suggesting abnormalities analogous to non-motor features of PD (Jellinger 2011; McDowell and Chesselet 2012; Smith et al. 2012).
Central to this work is the availability of validated methods to evaluate olfaction, gastrointestinal function, sleep disturbances, or depression/anxiety in experimental animals. The technical difficulties of reliably determining the presence or absence of these non-motor features in experimental animals are not trivial. Furthermore, the mechanistic relationship between abnormalities observed in the commonly used assays in experimental animals and the analogous symptoms in human patients is uncertain, especially for complex behavioral traits such as depression and anxiety. Nonetheless, ways to evaluate these non-motor symptoms have been reported in mice, rats, primates, and zebrafish. Each of these animals shows phylogenetic conservation of neuroanatomical structures involved in early Braak stages of PD pathology, suggesting that they might be employed as models to study premotor PD.
So far, a number of animal models of PD have shown either non-motor functional abnormalities or pathology outside the substantia nigra. Olfactory function has been shown to be abnormal in MPTP-treated rodents (Schintu et al. 2009), transgenic mice expressing α-synuclein under a neuronal regulatory element derived from the Thy1 gene (Thy1-α Syn) (Fleming et al. 2008), and mice expressing reduced levels of the vesicular monoamine transporter (VMAT) (Taylor et al. 2009). Sleep and circadian rhythm are known to be disrupted in MPTP-treated rodents (Laloux et al. 2008), rotenone-treated rats (García-García et al. 2005), and Thy1-αSyn mice and VMAT2-deficient mice (Taylor et al. 2009). Gastrointestinal function has been shown to be abnormal in MPTP-treated mice (Anderson et al. 2007), rotenone-treated rats (Drolet et al. 2009), Thy1-αSyn mice (Wang et al. 2008, 2012), SNCA PAC mice (which expresss mutant human α-synuclein from a P1 artificial chromosome containing its endogenous regulatory elements) (Kuo et al. 2010), and VMAT2-deficient mice (Taylor et al. 2009). These findings are of interest because they demonstrate that toxicant exposures and genetic manipulations used to induce motor signs of PD can also induce non-motor features. This suggests that at least some of the neuronal populations underlying non-motor symptoms share susceptibility with dopamine neurons to agents implicated in motor PD pathogenesis. This is consistent with a model in which common etiological mechanisms could underlie both motor and non-motor components of the disease.
Interestingly, a few of the models have shown ordered progression from non-motor to motor symptoms. Thy1-αSyn transgenic mice showed α-synuclein inclusions in the olfactory bulb and deficits in olfactory function on multiple tests by 3 months of age (Fleming et al. 2008). By this time point, animals also showed progressively worsening sleep abnormalities (Kudo et al. 2011) and progressive reduction in stool frequency (Wang et al. 2012). These changes preceded loss of striatal dopamine, which did not occur until 14 months of age (Lam et al. 2011). Similarly, VMAT2-deficient mice demonstrated progressive non-motor symptoms prior to the onset of motor deficits (Taylor et al. 2009). Gastrointestinal dysfunction was seen at 2 months of age, olfactory defects by 5 months, and anxiety-like behavior at 6 months. L-dihydroxyphenylalanine (L-DOPA)–responsive hypokinesia and loss of striatal tyrosine hydroxylase terminals were present by 18 months of age, and loss of nigral dopamine neurons worsened between 18 and 24 months (Caudle et al. 2007). Data from both models imply that a systemic abnormality affecting all cells can result in specific abnormalities of neuronal populations implicated in non-motor and motor PD with replication of some of the temporal course.
These data do not yet allow us to distinguish between a model for pathogenic progression in which the temporal course of the disease is dictated by the differential vulnerability of various neuronal groups to a systemic abnormality and an alternative model in which pathology spreads anatomically from one site of the nervous system to another to produce progressive symptoms. Much recent attention has been given to the idea that α-synuclein has prion-like properties and that α-synucleinopathy can spread from a site of initial pathology to other regions of the central nervous system (CNS) by axonal transport and cell-to-cell spread (Luk et al. 2012). In this regard, it is noteworthy that the pathology in both Thy1-αSyn mice (Fleming et al. 2004) and VMAT2-deficient mice (Taylor et al. 2009) is dependent on the presence of α-synuclein. However, several alternative explanations for the progression of disease are equally consistent with the available data and further studies will be necessary to determine whether progression can be arrested by interventions that prevent the transport or transmission of pathological α-synuclein species, or whether additional cellular factors dictate the differential vulnerability of neuronal groups involved in non-motor symptoms.
The hypothesis that an environmental agent could provoke pathology at an anatomical site of entry that then progresses to involve other structures, culminating in degeneration of the substantia nigra, has received some preliminary experimental support. For example, Jang et al. (2009) reported that, in mice, intranasally injected H5N1 influenza virus travelled from the enteric nervous system (ENS) into the CNS and eventually caused degeneration of dopaminergic neurons. Further, this sequence was accompanied by chronic neuroinflammation with microglial activation and elevated expression of cytokines and other proinflammatory biomarkers (Jang et al. 2012). These findings imply that initiating pathogenic events can provoke distinct secondary mechanisms underlying disease progression, with the important implication that environmental agents that trigger early events in PD pathogenesis may no longer be present at the end stage of the disease, when tissue samples are generally available for analysis.
The gastrointestinal tract is potentially an important site for exposure to environmental agents, and the suggestion that α-synuclein pathology in the ENS may be one of the first abnormalities in PD patients has promoted interest in the possibility of modeling pathology in the ENS and its subsequent progression to the CNS. Transgenic mice expressing human α-synuclein under its own regulatory elements showed prominent ENS pathology, but no progression to other features of PD (Kuo et al. 2010), suggesting that a second event was necessary to promote disease progression. Recent reports showed that intragastric rotenone caused α-synuclein aggregation in mice, following a staged pattern that was consistent with the Braak hypothesis (Pan-Montojo and Funk 2010; Pan-Montojo et al. 2010), and resection of the autonomic nerves prevented this progression (Pan-Montojo et al. 2012). These interesting observations are yet to be replicated by other laboratories, and their interpretation consequently remains speculative. However, the local microenvironment of the gastrointestinal tract remains a potentially significant factor in dictating initiating pathogenic events, and is worthy of further investigation. This might also encompass evaluation of the role of the gut microbiome, which could be experimentally manipulated in animal models to determine whether alterations can initiate PD pathology or modulate the time course of onset of pathology and progression. Although few empirical data exist regarding the role of the microbiome in PD, the microbiome influences the immune system, gastrointestinal mobility, and the metabolism of nutrients and other exogenous chemicals (Grenham et al. 2011), all of which may potentially contribute to the development of PD. Similarly, experimental animals could be exposed to toxicants through the gastrointestinal tract to evaluate whether etiologically implicated exogenous agents can provoke the earliest pathological changes of PD or modulate their appearance in experimental models. These studies could provide valuable mechanistic insights and generate further hypotheses to be addressed in human studies.
Finally, although this review focuses on PD, research on premotor symptoms may have broader implications because many of these symptoms have been linked to other neurological diseases. For example, hyposmia is associated with higher risk of cognitive decline and Alzheimer's disease (Wilson et al. 2007, 2009), and RBD precedes Lewy body dementia and multiple system atrophy (Schenck et al. 2013). Further, olfactory dysfunction has been documented in schizophrenic patients and individuals at high risk for schizophrenia (Moberg et al. 2013). Therefore research on premotor symptoms may eventually provide novel insights into the natural history and etiology of neurodegeneration and related conditions in addition to PD, and into the complex interrelationships among these conditions.
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