EARLY NONMOTOR SYMPTOMS AND THE CONCEPT OF PREMOTOR PD
It is now well recognized that nonmotor symptoms are an integral part of the clinical spectrum of the disease [43–46] and may even antedate the clinical manifestation of cardinal motor features of PD by several years in a substantial proportion of patients[7–9, 47] (Table 2). Considering Braak’s hypothesis that PD pathology first starts in extranigral sites, particularly the olfactory system, lower brainstem and peripheral autonomic nervous system [4, 5, 48], it is intriguing to note that recent clinical studies have found certain nonmotor symptoms such as constipation, dream enacting behaviour, and smell-loss preceding the onset of first motor complaints into time periods that are longer before motor onset as compared to other nonmotor complaints [7, 9].

Hyposmia
Olfactory detection, identification or discrimination deficits have consistently been found in approximately 80% of patients with PD [56, 57]. Although many patients retrospectively report smell loss prior to noting the first motor problems [7, 9], to date there are only two population based studies that have investigated prospective risk for PD in relation to baseline smell function [16, 17]. In the Honolulu-Asia Aging study (HAAS), a large cohort of more than 2000 men of Japanese ancestry was prospectively followed for PD incidence with respect to baseline olfactory performance using the Brief Smell Identification Test (B-SIT) [17]. After adjustment for age and other potential confounders, the odds ratio for incident PD within four years in those with the lowest quartile of B-SIT scores at baseline was 5.2 and 3.1 in the second lowest quartile as compared with the top two quartiles. However, hyposmia was not associated with PD risk beyond four years. Intriguingly, a clinicopathologic study in a subsample from the HAAS, found an association of olfactory dysfunction with incidental Lewy bodies in the SN [25]. Likewise, the PRIPS study, a large population-based cohort study on risk factors for incident PD (see imaging biomarkers), found a relative risk ratio of 6.5 in hyposmic participants over 3 years [16]. More recently, several studies have addressed the potential of hyposmia as a risk marker for PD in subjects with increased apriori risk for PD. For example, two recent prospective cohort studies of idiopathic RBD patients found that baseline olfactory dysfunction predicted incident Lewy body disorders over 5 and more years of follow-up [14, 58].

REM-sleep behavior disorder (RBD)
RBD is a parasomnia clinically characterized by dream-enacting behaviours related to loss of physiological atonia during REM-sleep [59]. The prevalence of idiopathic RBD in the population is not well defined as definite diagnosis requires polysomnography. A commonly cited figure of 0.4% , however, may well be an underestimate [60]. Indeed, when using two validated screening questionnaires in an elderly population-based sample of 476 subjects, we recently found a prevalence of probable RBD of 5–8% in a Caucasian population aged >60 years [61]. In this particular cross sectional study, probable RBD was associated with multiple other nonmotor markers of PD, while polysomnography was not available. Idiopathic RBD is increasingly recognized as a harbinger of neurodegenerative diseases, including not only PD but also other synucleinopathies like DLB or MSA. Several follow-up studies have found that the majority of subjects with idiopathic RBD (>80%) will convert into one of these disorders –most commonly PD or DLB - with extended follow-up over decades [15, 54, 62]. Two recent prospective cohort studies have further substantiated these observations. Postuma and colleagues collected follow-up data in a multicentre sample of 305 patients with idiopathic RBD over up to 6 years and found an overall conversion to neurodegenerative diseases of 33% [63], which was time-dependent at 15% after 2 years, 25% after 3 years, and 41% after 5 years. Conversion to PD or DLB was common (42% and 50% , respectively), while only 8% converted to MSA. Idiopathic RBD patient who converted over the observational period were older, more likely to report a family history of dementia, and more frequently endorsed autonomic and/or motor symptoms on questionnaires compared to those who remained disease free, whereas many baseline characteristics including caffeine and nicotine exposure were not different between these groups [63]. With the aid of thorough testing batteries, conversion from RBD to PD or PD Dementia/DLB appears to be more predictable. One recent prospective study in 89 idiopathic RBD patients found that smell identification loss (hazard ratio (HR) 2.8), abnormal colour vision (HR, 3.1), and subtle motor impairment (HR, 3.9), as well as advanced age (HR, 1.1) and non-use of anti-depressants (HR, 3.5) was associated with conversion to one of these synucleinopathies (including MSA) over the 7.5 year observational period.
Taken together, current evidence shows that RBD is the most specific among the different risk factors for PD (see Table 2) and RBD cohorts seem obvious candidates for future disease-prevention studies for PD. However, the median latency to conversion into clinically defined PD can be as long as 12 to 14 years [15, 54], seriously limiting the feasibility of such trials. Therefore, we recently investigated whether olfactory impairment can predict early conversion to PD or PDD/DLB among 35 idiopathic RBD patients prospectively followed over 5 years [58]. Indeed, abnormal baseline performance on the multidimensional SniffinSticks test assessing odour identification, odour discrimination, and olfactory threshold predicted conversion to a Lewy body disorder with an accuracy of 82.4% , and this was also true for poor performance on the identification subscore only. Based on the findings from this cohort, sample sizes for a hypothetical neuroprotection trial in RBD with conversion to a Lewy body disorders as an endpoint could be reduced by 74–80% for a 5-year trial if idiopathic RBD patients were pretested for baseline olfactory dysfunction. For example, a total of 760 patients with idiopathic RBD versus 188 patients with idiopathic RBD and olfactory dysfunction would be required to have an 80% chance to detect a 30% decrease in the primary outcome measure of conversion to a Lewy body disease [58]. Similar data were also reported by Postuma et al. who found that by excluding idiopathic RBD subjects <55 years of age or using antidepressants reduced estimated sample sizes for 3-year neuroprotection trials with the same outcome measure by ≥25% when further pretesting for olfactory dysfunction, impaired colour vision, or subtle motor impairment and by ≥40% when using combinations of these markers [14].

Constipation
Constipation is common in PD affecting 28–61% of patients [46]. In the Honolulu-Asia Aging study men with bowel movement frequencies of less than once per day had a relative risk for incident PD of at least 2.7 compared to men with more frequent bowel function [10]. The brains of 245 subjects from this cohort were available for post-mortem examination and –consistent with the above finding –there was a significant association of constipation in life with the prevalence of incidental Lewy Bodies in the SN at post-mortem: 24.1% of those who had reported less than 1 bowel movement per day had this pathologic feature as compared to 6.5% of those with bowel movement frequencies of greater than 1 per day [65]. Interestingly, several studies have recently reported on findings of synuclein-immunostaining in the enteric nervous system of PD subjects using colonic biopsies providing a possible link between colonic dysmotility and synuclein-related neurodegeneration in PD [65, 66]. However, specificity for PD seems to be rather low (see below under tissue biomarkers).
Intriguing as these associations are, none of the nonmotor symptoms discussed above in themselves have sufficient specificity to qualify for screening for PD risk in the population. While sensitivity for future PD can be as high as 80% for features like hyposmia or constipation, their specificity is low [47]. Although specificity and predictive value of idiopathic RBD for PD risk are much higher, sensitivity is quite low. In addition, for low prevalence disorders like PD, by definition positive predictive values of any of the features discussed are small and would only be in the order of 50% even for markers of 99% specificity [67]. Therefore, future screening tools to narrow down at-risk populations for PD will likely require the use of multiple markers potentially including imaging and molecular biomarkers.