Premotor Symptoms and Early Diagnosis of Parkinson's Disease

ABSTRACT

Parkinson's disease is a disorder characterized by the motor findings of bradykinesia, rest tremor, cogwheel rigidity, and postural instability. As the disease progresses, most patients develop numerous nonmotor signs and symptoms, many of which play a major role in reducing quality of life. What is becoming increasingly clear is that nonmotor findings, including hyposmia, sleep disorders, autonomic abnormalities, cognitive changes, and neurobehavioral changes, often precede the motor findings.

KEYWORDS: :

• autonomic disorders
• cognitive impairment
• depression
• olfaction

INTRODUCTION

Parkinson's disease (PD) is a neurodegenerative disorder of unknown etiology that has no cure. It is a progressive disorder traditionally characterized by the motor findings of bradykinesia, rest tremor, cogwheel rigidity, and postural instability. From a neuropathological standpoint, the diagnosis of PD is made when there is neuronal loss in the substantia nigra and intraneuronal inclusions called Lewy bodies are found. The neurochemical hallmark of PD is dopamine loss in the nigrostriatal dopamine system. It is clear that these pathological and neurochemical findings correlate extremely well with the motor features. Unfortunately, by the time the motor features of PD become clinically apparent, there is upward of 60% loss of dopamine neurons in the nigrostriatal pathway. Therefore, interventions aimed at slowing or stopping disease progression may not have been effective, given the high degree of neuronal damage already present at the time of diagnosis.

This has led to the goal of finding biomarkers that identify a group of individuals at risk to develop PD prior to their showing motor signs of the disease. It has become increasingly clear that there are many nonmotor clinical findings that precede the onset of motor PD and that a battery of nonmotor testing might be used to identify this at-risk group. The purpose of this review is to describe some of the nonmotor signs and symptoms of PD and discuss the possibility of an earlier diagnosis.

OVERVIEW

The concept that PD is not a single disease but is a syndrome with multiple possible etiologies appears clear. Much of this comes from the finding that there are multiple genetic mutations that can lead to similar motor features of bradykinesia, rest tremor, and rigidity [1, 2]. Additionally, it has been proposed that there is a Parkinson's complex that includes not only motor parkinsonism but also multiple nonmotor symptoms including hyposmia, sleep disorders, autonomic abnormalities, cognitive changes, and neurobehavioral changes [3]. Langston has described these nonmotor findings as being the “tip of the iceberg” [3].

OLFACTION

Hyposmia or anosmia is a symptom that almost all PD patients will acknowledge. Most will state that this has been present for many years and often predates motor symptoms. One study found 96.7% of PD patients had hyposmia or anosmia, although when adjusted for age this became 74.5% [4]. Research showing that olfaction was impaired in PD began in the 1970s [5], and early studies of olfactory detection and discrimination found that the abnormalities in PD were not correlated with age, gender, disease severity, disease duration, treatment, motor fluctuations, or intellectual function [6,7]. One longitudinal study found conflicting results as to whether olfaction worsened over time [8].

Olfactory discrimination diminishes with age [9, 10]. Cross-sectional studies have clearly shown that hyposmia is a highly sensitive finding in PD, but it is not specific. Olfaction is also impaired in dementia with Lewy bodies (DLB) [11, 12], pure autonomic failure [13], and amyotrophic lateral sclerosis, with mixed results found for Alzheimer's disease and multiple system atrophy [11, 12]. Therefore, this nonmotor finding may be used as a premotor test to identify an at-risk group for PD, but it is certainly not diagnostic. The finding of hyposmia differentiates PD from some other parkinsonian disorders such as progressive supranuclear palsy [14] and vascular parkinsonism [15], and normal olfaction is found in most studies of essential tremor [16–19].

Multiple methods have been used to assess olfaction with two of the more common current methods being the University of Pennsylvania Smell Identification Test [20], which measures odor discrimination, and Sniffin Sticks [21], which measures odor thresholds, odor discrimination, and odor identification.

VISUAL CHANGES

While many patients with PD complain of blurred vision or nonspecific difficulties with vision, objective measures of color discrimination and contrast sensitivity may be useful for making an early diagnosis of PD. The Farnsworth-Munsell 100-hue test measures color discrimination by having the subject arrange colored discs in sequence between pairs of reference discs and calculating a total error score [22]. Subscores can be generated for blue-yellow and red-green. Multiple studies have shown that patients with PD have more errors than a control population [23], and that this may be an early finding as it occurs in early, untreated patients [22,24]. Similarly, abnormalities in contrast sensitivity are present in PD and appear to be correlated with disease severity [25]. Both color discrimination and contrast sensitivity may relate to dopamine activity in the retina but that remains unclear. One study found that color discrimination correlated with disease severity but did not correlate with β-CIT SPECT (single photon emission computed tomography) scan measures in 31 de novo PD patients [26]. There is evidence for progression of abnormalities in color discrimination [27, 28] and contrast sensitivity [28]. The use of the Farnsworth-Munsell test however needs to take into consideration motor function as there was a correlation between fine motor performance and color discrimination in one study [29]. Additionally, dopaminergic treatment may affect both color discrimination and contrast sensitivity [30, 31].

Optical coherence tomography (OCT) is a method for measuring retinal thickness. PD patients have reduced retinal nerve fiber layer thickness [32–35] as well as perimacular inner retinal layer thickness [34]. One small, recent OCT study has shown that the fovea was thinner in PD than in essential tremor [36].

AUTONOMIC DYSFUNCTION

Constipation

Constipation is an extremely frequent complaint of patients with PD and often predates the motor symptoms. In the Honolulu Aging Study, men with <1 bowel movement per day had a 2.7-fold increased risk of developing PD than those with 1 bowel movement per day and a >4-fold increased risk compared with those with ≥2 bowel movements per day [37]. In a case-control study of 196 PD subjects and matched controls, constipation was more common (odds ratio = 2.48) in PD cases preceding the onset of PD than in the controls [38].

There appears to be some evidence for a pathological explanation to constipation in PD. Lewy bodies were found in the myenteric plexus of the colon in a patient with megacolon [39], and in the esophagus and colon in two cases with dysphagia [40]. In a study of α-synuclein staining in multiple regions of the gastrointestinal (GI) tract, the esophagus was more commonly affected than the colon [41]. Additionally, the dorsal motor nucleus of the vagus provides preganglionic parasympathetic innervation to the GI organs and this area is one of the first involved in PD [42,43].

Cardiac Abnormalities

Autonomic dysfunction can also be found on cardiac evaluation of patients with PD. There is myocardial postganglionic sympathetic dysfunction in PD as measured by ¹²³I-meta-iodobenzyl guanidine (MIBG) cardiac scintigraphy [44,45]. These abnormalities were found very early in the disease [46] and were unrelated to disease severity and medication in one study [44], although another found a relationship to disease severity [47]. There is recent evidence that α-synuclein pathology was present in neurites of the epicardium in PD-autopsied subjects as well as a reduction in tyrosine hydroxylase (TH) immunohistochemistry that identifies dopamine-containing neurons [48].

Orthostatic Hypotension

While parkinsonism with orthostatic hypotension often is the hallmark of multiple system atrophy, patients with idiopathic PD often suffer from orthostasis. Not commonly thought to be an early finding in PD, one study found that of 51 patients with early, untreated PD, 7 (14%) had orthostatic hypotension (>20 mmHg decrease in systolic BP) [49].

Heart Rate Variability (HRV)

In a study of 26 untreated PD cases having sleep evaluations, there was evidence for defective cardiac autonomic control, suggesting this may be an early diagnostic marker [50]. A study comparing HRV in untreated PD and control subjects found that HRV was decreased in PD when the patients were awake and while asleep [51]. A decrease in HRV in PD patients was found in those without any autonomic symptoms [52].

SLEEP DISORDERS

While sleep disorders worsen as PD advances, it is clear that some sleep issues predate the motor findings of PD. Excessive daytime sleepiness (EDS) is a very nonspecific complaint that may have multiple causes. However, there may well be an increase in this complaint prior to motor findings in PD. In the Honolulu Aging Study, 3,078 men were evaluated and followed longitudinally [53]. The odds ratio for the development of PD was 3.3 for men with EDS compared with those without EDS [53]. Thus, assessing for this symptom as part of a battery to identify at-risk people for PD may be worthwhile.

There are data that suggest that rapid eye movement (REM) sleep behavior disorder (RBD) is a synucleinopathy [54–56]. There is a high occurrence of RBD in patients with PD, up to 60% in some studies [57,58], and up to 80% in DLB patients [59]. On the flip side, longitudinal studies have shown that up to 65% of patients with idiopathic RBD go on to develop PD or DLB, and that the RBD can predate these disorders by decades. There is also mounting evidence in the RBD literature that many of the nonmotor symptoms that occur in PD also occur in RBD. Multiple studies have shown that RBD cases have hyposmia [60–62], with Postuma et al. [61] also finding deficits in color discrimination compared with a control population. Using questionnaires, they also found autonomic dysfunction with abnormalities in constipation, erectile dysfunction, and urinary scores [61].

Cardiac abnormalities in PD have been discussed above. Recent studies have now shown that RBD cases have abnormalities in ¹²³I-MIBG scintigraphy that may be more severe than in PD [47,63]. Additionally, PD cases with RBD have been found to have more severe abnormalities in ¹²³I-MIBG scintigraphy than those without RBD [64]. Also discussed above were the findings that PD patients had abnormalities in HRV. A recent study has found that patients with RBD (n = 11) had significantly decreased HRV in wakefulness compared with controls (n = 11) [65].

COGNITIVE DISORDERS

While it is clear that cognitive impairment and dementia are major factors in advanced PD, the literature is growing regarding cognitive abnormalities in early, untreated PD patients. In a study of 142 PD cases that completed a short battery of neuropsychological tests, 35.2% were considered to have some cognitive impairment [66]. Another study of 115 early, untreated PD cases compared with 70 controls found 23.5% of the PD and 4.3% of the controls were cognitively impaired, using a neuropsychological test battery [67]. This has been followed by a study of 196 untreated PD patients and 201 controls that found the PD cases to be impaired on all tests in the battery, with 19% meeting criteria for mild cognitive impairment [68]. These findings suggest that assessments of cognitive function may be useful in a battery used to identify early or at-risk subjects for PD.

NEUROBEHAVIORAL CHANGES

As with a number of the other nonmotor findings discussed above, many patients with advancing PD develop neurobehavioral findings. These may include depression, anxiety, and psychosis. However, in a case-control study of 196 incident PD cases and matched controls, the odds ratio for anxiety in PD was 2.2, for depression it was 1.9, and for both it was 2.4 [69]. In an epidemiological study of 105,416 subjects at the time of diagnosis of PD, 9.2% of the patients had a previous history of depression, whereas only 4% of the controls had depression with an odds ratio of 2.4 [70]. While depression and anxiety are not uncommon in the general population, these associations with premotor PD suggest that they may be useful as part of a battery for identifying at-risk individuals. They also need to be addressed from a clinical standpoint as they do influence quality of life [71].

INCIDENTAL LEWY BODY DISEASE

It is clear that depending on the age of the cohort studied, up to 25% of autopsied control subjects have evidence for Lewy bodies on neuropathological evaluation [72–74]. These cases are called incidental Lewy body disease (ILBD), and in antemortem studies, these cases do not appear to have motor findings that would suggest early PD [75]. However, it has been shown that in cases of ILBD, there is a decrease in TH activity in the striatum (the hallmark of PD) as well as a decrease in cardiac tissue [76–78]. Another study found not only a reduction in TH activity in ILBD epicardium but also a reduction in α-synuclein neurites in the epicardium [48]. Thus, nonmotor signs may well occur prior to motor signs and may already indicate pathological or neurochemical changes in the central nervous system (CNS) and peripheral nervous system (PNS).

Braak et al. [42] described a staging for Lewy body disorders that included two stages (Stages 1 and 2) that revealed Lewy bodies in the olfactory bulb and medulla but not yet in the substantia nigra. In a more recent article describing the Unified Lewy Body Staging System, Beach et al. [43] classify some cases as having Lewy bodies in the olfactory bulb only (Stage I) and others with other brainstem predominant (Stage IIa) or limbic predominant (Stage IIb). In both these staging systems, there are cases where no motor features of PD are present, yet the pathological hallmark of PD, Lewy bodies, are present, just not in the region (substantia nigra) where motor features are thought to be controlled. Additionally, using α-synuclein staining, Beach et al. [41] have found phosphorylated α-synuclein histopathology in the spinal cord, parasympathetic ganglia, vagus nerve, lower esophagus, and submandibular gland. These findings may well explain a number of the nonmotor symptoms that precede motor PD.

SUMMARY

It is now quite clear that PD is not solely a disorder of movement and that nonmotor symptoms and signs often precede the motor findings. The importance of these nonmotor features include their potential to be biomarkers for early diagnosis as well as the potential effect they have on quality of life and therefore the need to appropriately diagnose and treat them.

Declaration of interest: Dr. Charles H. Adler has received consulting fees in the past 2 years from Biogen Idec, Eli Lilly, Ipsen, Merck Serono, and Merz.