Research on the Premotor Symptoms of Parkinson’s Disease: Clinical and Etiological Implications

“The hypothesis that premotor symptoms precede the motor signs of PD is broadly compatible with neuropathological findings reported by Braak et al. (2003).”

“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).”

“…for pathogenic 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).”

“For example, several clinical studies have consistently documented RBD onset about 10–20 years before PD onset (Boeve and Saper 2006; Claassen et al. 2010; Iranzo et al. 2006; Postuma et al. 2009; Schenck et al. 1996).”

“Accumulating epidemio logical 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;…”

“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…”

“…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…”

“…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…”

“The study was designed to evaluate a two-stage strategy of at-risk identification: olfactory testing using the University of Pennsylvania Smell Identification Test (Doty et al. 1984), followed by dopamine-transporter (DAT) imaging.”

“For example, several studies showed that constipation might precede PD clinical diagnosis by 10–20 years in men (Abbott et al. 2001; Gao X et al. 2011; Savica et al. 2009), but data are not consistent in women (Gao X et al. 2011; Savica et al. 2009).”

“For example, hypos-mia 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).”

“A recent meta-analysis also confirmed that constipation and mood disorders were associated with higher risk of PD (Noyce et al. 2012).”

“Accumulating epidemio logical 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;…”

“…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).”

“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 Figure 1.”

“…showed that intra gastric 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).”

“…[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).”

“In this regard, it is noteworthy that the pathology in both Thy1-α Syn mice (Fleming et al. 2004) and VMAT2-deficient mice (Taylor et al. 2009) is dependent on the presence of α -synuclein.”

“For example, Jang et al. (2009) reported that, in mice, intra-nasally injected H5N1 influenza virus trav-elled from the enteric nervous system (ENS) into the CNS and eventually caused degeneration of dopaminergic neurons.”

“Further, α -synuclein was identified from colon tissues of PD patients collected 2–5 years before PD motor onset (Shannon et al. 2012), but not in any of the controls.”

“Several screening questionnaires for probable RBD (Boeve et al. 2011; Li et al. 2009; Postuma et al. 2012a; Stiasny-Kolster et al. 2007) have been developed and validated in clinical settings, but their validities in identifying RBD patients from the general population are yet to be evaluated.”

“Accumulating epidemio logical 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;…”

“Does pathology progress anatomically, as the Braak hypothesis predicts (Pan-Montojo et al. 2012)?”

“Hyposmia was evaluated using the Sniffin’ Stick test (Hummel et al. 2001) and SN+ by trans cranial sonography.”

“…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…”

“Accumulating epidemio logical 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;…”

“…defects by 5 months, and anxiety-like behavior at 6 months. l-dihydroxyphenylalanine (l-DOPA)– responsive hypo kinesia 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).”

“Several screening questionnaires for probable RBD (Boeve et al. 2011; Li et al. 2009; Postuma et al. 2012a; Stiasny-Kolster et al. 2007) have been developed and validated in clinical settings, but their validities in identifying RBD patients from the general population are yet to be evaluated.”

“2008), although current smoking is associated with a higher risk of hyposmia in some studies (Schubert et al. 2012; Vennemann et al. 2008).”

“However, because most premotor symptoms are common in the elderly and are etiologically heterogeneous (Doty 2009; Leung et al. 2011), novel approaches are needed to assess various modalities of these symptoms and to identify patterns that are more specific to PD. Compared to other premotor…”

“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).”

“For example, hypos-mia 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).”

“…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.”

“Several screening questionnaires for probable RBD (Boeve et al. 2011; Li et al. 2009; Postuma et al. 2012a; Stiasny-Kolster et al. 2007) have been developed and validated in clinical settings, but their validities in identifying RBD patients from the general population are yet to be evaluated.”

“Accumulating epidemio logical 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;…”

“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-α Syn mice and VMAT2-deficient mice (Taylor et al. 2009).”

“In adults, the prevalence of constipation is higher in women and increases modestly with age (McCrea et al. 2009; Suares and Ford 2011).”

“Gastrointestinal function has been shown to be abnormal in MPTP-treated mice (Anderson et al. 2007), rotenone-treated rats (Drolet et al. 2009), Thy1-α Syn mice (Wang et al. 2008, 2012), SNCA PAC mice (which expresss mutant human α -synuclein from a P1 artificial chromo some containing its…”

“Several important studies have tested the hypothesis that premotor symptoms, coupled with neuro imaging, may lead to early identifi ca tion, or even diagnosis, of PD (Lang 2011; Tolosa et al. 2009).”

“…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).”

“Two other studies among high-risk individuals (Ponsen et al. 2009; Postuma et al. 2011) showed that hyposmia predicted PD risk throughout the entire follow-up period of 5 years.”

“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…”

“Gastrointestinal function has been shown to be abnormal in MPTP-treated mice (Anderson et al. 2007), rotenone-treated rats (Drolet et al. 2009), Thy1-α Syn mice (Wang et al. 2008, 2012), SNCA PAC mice (which expresss mutant human α -synuclein from a P1 artificial chromo some containing its…”

“Further, PD is likely to be phenotypically and etiologically hetero geneous (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.”

“For example, hypos-mia 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).”

“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-α Syn mice and VMAT2-deficient mice (Taylor et al. 2009).”

“In support of this notion, in the HAAS, both the sense of smell (Ross et al. 2006) and bowel movement frequency (Abbott et al. 2007) were strongly related to incidental Lewy body disease among individuals without PD.”

“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…”

“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 Figure 1.”

“In support of this notion, in the HAAS, both the sense of smell (Ross et al. 2006) and bowel movement frequency (Abbott et al. 2007) were strongly related to incidental Lewy body disease among individuals without PD.”

“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 Figure 1.”

“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).”

“…[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).”

“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).”

“Non-Parkinsonian family members of patients with the leucine-rich repeat kinase 2 ( LRRK2 G2019S) mutation showed more constipation and poorer color discrimination than controls (Marras et al. 2011).”

“In adults, the prevalence of constipation is higher in women and increases modestly with age (McCrea et al. 2009; Suares and Ford 2011).”

“More than 1 million older U.S. adults live with PD, and the number will double by the year 2030 (Bach et al. 2011).”

“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).”

“For example, Mirelman et al. (2011) reported subtle gait changes among asymptomatic carriers of LRRK2 mutation with quantified gait analyses under challenged conditions.”

“Further, olfactory dysfunction has been documented in schizophrenic patients and individuals at high risk for schizophrenia (Moberg et al. 2013).”

“Several important studies have tested the hypothesis that premotor symptoms, coupled with neuro imaging, may lead to early identifi ca tion, or even diagnosis, of PD (Lang 2011; Tolosa et al. 2009).”

“…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…”

“…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…”

“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).”

“Two other studies among high-risk individuals (Ponsen et al. 2009; Postuma et al. 2011) showed that hyposmia predicted PD risk throughout the entire follow-up period of 5 years.”

“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…”

“Preliminary results have been published from the Prospective Evaluation of Risk Factors for Idiopathic Parkinson’s Syndrome (PRIPS) study (Berg et al. 2013) and the Parkinson At-Risk Syndrome (PARS) study (Siderowf et al. 2012).”

“…function has been shown to be abnormal in MPTP-treated mice (Anderson et al. 2007), rotenone-treated rats (Drolet et al. 2009), Thy1-α Syn mice (Wang et al. 2008, 2012), SNCA PAC mice (which expresss mutant human α -synuclein from a P1 artificial chromo some containing its endogenous…”

“Further, this sequence was accompanied by chronic neuro-inflammation with microglial activation and elevated expression of cytokines and other pro-inflammatory biomarkers (Jang et al. 2012).”

“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).”

“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).”

“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 Figure 1.”

“Does the selectivity and order of neuro degeneration in PD reflect differential sensitivity to environmental agents or some other mechanism of progression such as prion-like spreading (Dunning et al. 2012)?”

“Accumulating epidemio logical 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;…”

“…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…”

“A large prospective study reported subjective complaints of motor dysfunctions such as stiffness and tremor prior to PD diagnosis (de Lau et al. 2006).”

“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).”

“…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).”

“…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.”

“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 Figure 1.”

“…(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),…”

“2008), rotenone-treated rats (García-García et al. 2005), and Thy1-αSyn mice and VMAT2-deficient mice (Taylor et al.”

“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-α Syn mice and VMAT2-deficient mice (Taylor et al. 2009).”

“Further, PD is likely to be phenotypically and etiologically hetero geneous (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.”

“…showed that intra gastric 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).”

“…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).”

“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).”

“…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…”

“[20] Chen H, Burton EA, Ross GW, Huang X, Savica R, Abbott RD, et al.”

“Environmental exposure to herbicides and pesticides have been associated with an increased risk of PD and high levels of α-synuclein in the brain (Chen et al., 2013; Goldman, 2014; Tanner et al., 2011).”

“Such assessment in the prodromal stage of PD may further help to better identify populations at risk despite that individual NMS are mostly not specific to PD [15].”

“Parkinson’s disease (PD) is a progressive neurodegenerative disease, which remains at a prediagnostic/precursor stage for many years, exhibiting isolated nonmotor or, later on, subtle motor features of the disease.(1) Based on this perspective, the International Parkinson and Movement Disorder Society (MDS) recently p…”

“Parkinson’s disease is, however, increasingly recognized as a systemic disease that may start in the periphery such as the gut.(28) Thus, higher plasma cholesterol may be protective in early PD development via peripheral mechanisms.”

“Thus, it has been hypothesized that exposure to environmental contributors to disease risk occurs years before the disease diagnosis.(7) This concept is supported by observations with pesticide exposure and PD risk.”

“Of interest, we also saw similar but often smaller sex differences in cognition among controls, suggesting these are likely intrinsic sex differences that may be further exacerbated by the onset of PD.”

“5) and can predate PD by over a decade [50,51].”

“In the prodromal phase of PD, the dual-task paradigm is used to exhaust compensation strategies aimed at preserving the motor function when the basal ganglia system is altered (Chen et al. 2013; Lerche et al. 2014).”

“In addition to the typical movement disorders, PD patients also suffer from various nonmotor manifestations, such as constipation [12, 13].”

“It is well established that PD has a highly variable phenotype, with a wide range of age at onset and progression of motor and nonmotor signs (Hoehn and Yahr 1991; Chen et al. 2013).”

“Lewy bodies containing alphasynuclein were found to be widespread outside the central nervous system in PD, particularly in regions that correlated with many of the early findings of autonomic and enteric nervous system dysfunction that predate the typical motor signs of striatal dopamine depletion and substantia nigr…”

“Environmental exposure to herbicides and pesticides increases the risk of developing PD 29 .”

“Sensory and visual symptoms have been previously reported, even though motor symptoms are the most common.(1,2) Dopamine is known to act as a neurotransmitter for visual processing in the retina, as dopaminergic amacrine cells have been found in the human retina, providing visual input to the retinal ganglion cells (R…”

“The common non-motor symptoms include depression and anxiety, constipation, hyposmia, and sleep disturbances (Chen et al., 2013).”

“While the prodromal period may provide an opportunity for early intervention once reliable identification methods have been developed, sensitivity and specificity of the prodromal symptoms still needs to be determined (Chen et al., 2013).”

“, constipation, delayed gastric emptying, and oesophageal dysfunction) [2], indicating a complex pathogenetic mechanism that over time converges toward a full-blown disease.”

“Although challenging, prodromal PD presents a major opportunity to improve our understanding of disease etiology [28] (Fig.”

“Increasingly however, the nonmotor symptoms of Parkinson's (loss of sense of smell, depression, anxiety, pain, bladder and bowel problems, panic attacks et cetera) are being recognised as key parts of the overall symptomatology (Chen et al., 2013).”

“NMSs often pre-date motor symptoms by 10–15 years, most notably depression or apathy, constipation, hyposmia, rapid eye movement (REM), and sleep behavior disorder (RBD) [24].”

“Some animal models of PD have shown also non-motor features and abnormalities outside of the substantia nigra such as abnormal olfactory function, gastrointestinal problems and sleep disorders ([11] and references therein).”

“While patients in the premotor stage of PD exhibit no motor symptoms, they have do demonstrate various prodromal nonmotor symptoms [23,29].”

“Thus, there is an emerging concept that premotor symptoms represent intermediate phenotypes before overt PD and may offer a vehicle to understand the role of genetics and the environment in the early stages of PD development.(4) As such, a detailed understanding of these nonmotor features and -------------------------…”

“In the absence of common pathogenesis, these symptoms also occur, but they are unlikely to cluster in the same individual.(13) Therefore, the presence of multiple premotor symptoms may be much more specific in predicting PD than individual symptoms.”

“Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by bradykinesia, rest tremor, rigidity, and postural instability.([1,2,3,4,5,6]) Parkinsonian tremor (oscillatory movement) is the central symptom of PD, presenting in about 70% of PD patients.”

“Neuropsychiatric symptoms, such as depression and anxiety [2,3], are likely to occur long before a PD diagnosis and can negatively impact the quality of life of people living with Parkinson’s (PwPs) and their care partners [4].”

“The association of NMS with motor PD has been recognised since the disease was first identified – in his original essay on PD, James Parkinson described several non-motor issues, including sleepiness and autonomic dysfunction.1 NMS often pre-date motor symptoms by 10–15 years2–4 and research on this topic has revealed…”

“However, other non-motor symptoms, such as cognitive impairment, may be present during the diagnosis of PD but may become more prominent in later stages (Gatt et al., 2016; Aarsland et al., 2021; Sveinbjornsdottir, 2016; Chen et al., 2013; Fang et al., 2020).”

“9%) with one symptom.(1) “Research on premotor symptoms is really in its infancy,” says Chen, who along with his colleagues suggests that large prospective cohort studies with lengthy follow-ups are needed to evaluate the role of premotor symptoms in PD development.”