Research on the Premotor Symptoms of Parkinson's Disease
Research on the Premotor Symptoms of Parkinson's Disease
Background: The etiology and natural history of Parkinson's disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years.
Objectives: We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications.
Methods: This review was based on a workshop, Parkinson's Disease Premotor Symptom Symposium, held 7–8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina.
Discussion: Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood.
Conclusion: This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and severely affects quality of life. More than 1 million older U.S. adults live with PD, and the number will double by the year 2030 (Bach et al. 2011). Clinical diagnosis of PD is currently based on the presence of motor dysfunction including rest tremor, bradykinesia, and rigidity. PD patients also suffer from a wide range of non-motor symptoms—including hyposmia (poor sense of smell), gastrointestinal dysfunction, psychiatric features (e.g., depression, anxiety, psychosis), sleep disorders, and mild-to-severe cognitive impairment—many of which are disabling and can be difficult to treat (Coelho and Ferreira 2012; Fernandez 2012) and greatly jeopardize the quality of life of PD patients (Storch et al. 2013). Pathologically, PD has been characterized by the loss of dopamine neurons in the substantia nigra pars compacta, which underlies motor dysfunction, and by the presence of Lewy bodies in selected regions of the brain.
The cardinal motor signs of PD become clinically evident when approximately 50% of the dopaminergic neurons in the substantia nigra are lost (Fearnley and Lees 1991). Despite symptomatic therapies for dopamine deficiency–related motor features, the disease continues to progress and often leads to severe mental and physical disabilities (Coelho and Ferreira 2012; Shulman et al. 2008) and increased mortality (Chen et al. 2006; Willis et al. 2012). To date, none of the available treatments can halt or reverse the pathological and clinical progression of PD, and novel strategies are needed. Research on disease-modifying strategies would be greatly assisted by the identification of high-risk populations.
Recent interest has focused on the non-motor symptoms of PD, some of which may predate motor signs and clinical diagnosis by years ("premotor symptoms" of PD). Accumulating epidemiological and clinical evidence suggests that hyposmia (Ross et al. 2008), constipation (Abbott et al. 2007; Gao X et al. 2011; Savica et al. 2009), depression (Bower et al. 2010; Fang et al. 2010; Ishihara-Paul et al. 2008; Shiba et al. 2000), anxiety (Bower et al. 2010; Ishihara-Paul et al. 2008; Shiba et al. 2000; Weisskopf et al. 2003), rapid eye movement sleep behavior disorder (RBD) (Claassen et al. 2010; Iranzo et al. 2006; Postuma et al. 2009; Schenck et al. 1996), excessive daytime sleepiness (EDS) (Abbott et al. 2005; Gao J et al. 2011), and autonomic dysfunction (Goldstein 2010) may occur well before the appearance of the classic motor dysfunction of PD. Evidence comes primarily from large prospective population-based cohort studies that were initially established for research on cancer and cardiovascular disease, such as the Honolulu Asia Aging Study (HAAS) (Ross et al. 2008) and the Health Professionals Follow-up Study (Gao X et al. 2011), and from retrospective examinations of archived medical records of PD cases and controls such as the Rochester Epidemiology Project (Savica et al. 2009). These findings are summarized in Table 1. A recent meta-analysis also confirmed that constipation and mood disorders were associated with higher risk of PD (Noyce et al. 2012). Hyposmia, RBD, and EDS were not included in this meta-analysis because risk estimates either were not available or were available from only one study.
The hypothesis that premotor symptoms precede the motor signs of PD is broadly compatible with neuropathological findings reported byBraak et al. (2003). This work, although controversial (Burke et al. 2008), suggests that deposition of α-synuclein in the form of Lewy bodies and Lewy neurites develops in the PD brain in six sequential stages. α-Synuclein pathology begins in the dorsal motor nucleus of the vagus and glossopharyngeal nerves and the anterior olfactory nucleus in stage 1, extends to the locus ceruleus and caudal raphe nuclei in the pons (stage 2), then to the substantia nigra (stage 3), to the temporal mesocortex (stage 4), and finally to the neocortex (stages 5–6). A later extension of this hypothesis further posits that the synucleinopathy may even first develop in the enteric nerves in the gut and later spread along the vagus nerve into the brain (Hawkes et al. 2007, 2009). Importantly, according to the Braak hypothesis, the irreversible loss of dopamine neurons in the substantia nigra and associated progressive motor dysfunction may not be evident until Braak stages 3 and 4. Although the Braak hypothesis is not universally supported (Burke et al. 2008; Dickson et al. 2010), it presents the intriguing possibility that the extra-nigra, nondopaminergic pathologies are intrinsic to early PD pathogenesis and that premotor symptoms could well be part of the disease's natural history (Hawkes et al. 2010).
Growing evidence on the importance of premotor symptoms, coupled with the Braak hypothesis, has generated substantial interest in understanding the origins and consequences of these symptoms. Clinical research primarily has focused on evaluating premotor symptoms and other factors as markers for the future development of PD, a subject elegantly reviewed by Berg et al. (2012). Another potential line of inquiry is based on the idea that the presence of multiple premotor symptoms in the same individual represents common underlying pathogeneses that may eventually lead to PD, and thus premotor symptoms may provide a unique opportunity to understand the etiology of PD (Hawkes et al. 2007, 2009). Despite this potential promise, little research has been carried out to understand the etiological implications of the premotor symptoms of PD.
This review was based on a workshop, Parkinson's Disease Premotor Symptom Symposium, held 7–8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina.
A comprehensive review of the clinical and epidemiological evidence for the existence of these premotor symptoms in PD is outside the scope of this review. Instead, we focus on outlining the promises and pitfalls of the concept of premotor symptoms and on developing research priorities and strategies for understanding the clinical and etiological implications of these symptoms. Although these symptoms can also develop after the clinical diagnosis of PD, for this review, we focus on the period prior to the emergence of diagnostic motor abnormalities.
Abstract and Introduction
Abstract
Background: The etiology and natural history of Parkinson's disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years.
Objectives: We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications.
Methods: This review was based on a workshop, Parkinson's Disease Premotor Symptom Symposium, held 7–8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina.
Discussion: Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood.
Conclusion: This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis.
Introduction
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and severely affects quality of life. More than 1 million older U.S. adults live with PD, and the number will double by the year 2030 (Bach et al. 2011). Clinical diagnosis of PD is currently based on the presence of motor dysfunction including rest tremor, bradykinesia, and rigidity. PD patients also suffer from a wide range of non-motor symptoms—including hyposmia (poor sense of smell), gastrointestinal dysfunction, psychiatric features (e.g., depression, anxiety, psychosis), sleep disorders, and mild-to-severe cognitive impairment—many of which are disabling and can be difficult to treat (Coelho and Ferreira 2012; Fernandez 2012) and greatly jeopardize the quality of life of PD patients (Storch et al. 2013). Pathologically, PD has been characterized by the loss of dopamine neurons in the substantia nigra pars compacta, which underlies motor dysfunction, and by the presence of Lewy bodies in selected regions of the brain.
The cardinal motor signs of PD become clinically evident when approximately 50% of the dopaminergic neurons in the substantia nigra are lost (Fearnley and Lees 1991). Despite symptomatic therapies for dopamine deficiency–related motor features, the disease continues to progress and often leads to severe mental and physical disabilities (Coelho and Ferreira 2012; Shulman et al. 2008) and increased mortality (Chen et al. 2006; Willis et al. 2012). To date, none of the available treatments can halt or reverse the pathological and clinical progression of PD, and novel strategies are needed. Research on disease-modifying strategies would be greatly assisted by the identification of high-risk populations.
Recent interest has focused on the non-motor symptoms of PD, some of which may predate motor signs and clinical diagnosis by years ("premotor symptoms" of PD). Accumulating epidemiological and clinical evidence suggests that hyposmia (Ross et al. 2008), constipation (Abbott et al. 2007; Gao X et al. 2011; Savica et al. 2009), depression (Bower et al. 2010; Fang et al. 2010; Ishihara-Paul et al. 2008; Shiba et al. 2000), anxiety (Bower et al. 2010; Ishihara-Paul et al. 2008; Shiba et al. 2000; Weisskopf et al. 2003), rapid eye movement sleep behavior disorder (RBD) (Claassen et al. 2010; Iranzo et al. 2006; Postuma et al. 2009; Schenck et al. 1996), excessive daytime sleepiness (EDS) (Abbott et al. 2005; Gao J et al. 2011), and autonomic dysfunction (Goldstein 2010) may occur well before the appearance of the classic motor dysfunction of PD. Evidence comes primarily from large prospective population-based cohort studies that were initially established for research on cancer and cardiovascular disease, such as the Honolulu Asia Aging Study (HAAS) (Ross et al. 2008) and the Health Professionals Follow-up Study (Gao X et al. 2011), and from retrospective examinations of archived medical records of PD cases and controls such as the Rochester Epidemiology Project (Savica et al. 2009). These findings are summarized in Table 1. A recent meta-analysis also confirmed that constipation and mood disorders were associated with higher risk of PD (Noyce et al. 2012). Hyposmia, RBD, and EDS were not included in this meta-analysis because risk estimates either were not available or were available from only one study.
The hypothesis that premotor symptoms precede the motor signs of PD is broadly compatible with neuropathological findings reported byBraak et al. (2003). This work, although controversial (Burke et al. 2008), suggests that deposition of α-synuclein in the form of Lewy bodies and Lewy neurites develops in the PD brain in six sequential stages. α-Synuclein pathology begins in the dorsal motor nucleus of the vagus and glossopharyngeal nerves and the anterior olfactory nucleus in stage 1, extends to the locus ceruleus and caudal raphe nuclei in the pons (stage 2), then to the substantia nigra (stage 3), to the temporal mesocortex (stage 4), and finally to the neocortex (stages 5–6). A later extension of this hypothesis further posits that the synucleinopathy may even first develop in the enteric nerves in the gut and later spread along the vagus nerve into the brain (Hawkes et al. 2007, 2009). Importantly, according to the Braak hypothesis, the irreversible loss of dopamine neurons in the substantia nigra and associated progressive motor dysfunction may not be evident until Braak stages 3 and 4. Although the Braak hypothesis is not universally supported (Burke et al. 2008; Dickson et al. 2010), it presents the intriguing possibility that the extra-nigra, nondopaminergic pathologies are intrinsic to early PD pathogenesis and that premotor symptoms could well be part of the disease's natural history (Hawkes et al. 2010).
Growing evidence on the importance of premotor symptoms, coupled with the Braak hypothesis, has generated substantial interest in understanding the origins and consequences of these symptoms. Clinical research primarily has focused on evaluating premotor symptoms and other factors as markers for the future development of PD, a subject elegantly reviewed by Berg et al. (2012). Another potential line of inquiry is based on the idea that the presence of multiple premotor symptoms in the same individual represents common underlying pathogeneses that may eventually lead to PD, and thus premotor symptoms may provide a unique opportunity to understand the etiology of PD (Hawkes et al. 2007, 2009). Despite this potential promise, little research has been carried out to understand the etiological implications of the premotor symptoms of PD.
This review was based on a workshop, Parkinson's Disease Premotor Symptom Symposium, held 7–8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina.
A comprehensive review of the clinical and epidemiological evidence for the existence of these premotor symptoms in PD is outside the scope of this review. Instead, we focus on outlining the promises and pitfalls of the concept of premotor symptoms and on developing research priorities and strategies for understanding the clinical and etiological implications of these symptoms. Although these symptoms can also develop after the clinical diagnosis of PD, for this review, we focus on the period prior to the emergence of diagnostic motor abnormalities.
