Nonmotor symptoms in Parkinson’s disease

Keywords::

• diagnostic criteria
• nonmotor symptoms
• Parkinson’s disease
• preclinical PD
• treatment

Prevalence & clinical spectrum

Parkinson’s disease (PD) is considered a paradigmatic movement disorder where parkinsonism, defined by the presence of bradykinesia plus at least one additional motor sign out of rest tremor, rigidity and impaired postural reflexes, is the anchor of current clinical criteria [1]. The neuropathological diagnosis of PD requires the presence of Lewy body degeneration with cell loss in the substantia nigra leading to striatal dopamine deficiency. The pathology of PD, however, is much more widespread, involving a multitude of brain areas beyond the nigrostriatal dopamine system, many of which are not primarily involved in motor control including brain stem nuclei such as the locus coeruleus, raphe nuclei, dorsal vagal nucleus and other ponto-medullary cell groups, the bulbus and tractus olfactorius and piriform cortex, large parts of the limbic and neocortex, the diencephalon, thalamus and also extend to the peripheral autonomic nervous system [2]. It is therefore not surprising that nonmotor symptoms (NMS) form an integral part of the clinical spectrum of PD: the PPRIAMO study – a multicenter assessment of NMS and their impact on quality of life in PD surveying more than 1100 patients with PD in different stages of their disease – found that overall 98.6% of the patients with PD reported the presence of one or several NMS [2]. NMS become more frequent with prolonged disease duration, and dementia, hallucinosis, depression, urinary incontinence and orthostatic hypotension were found in 50–80% of the patients with disease duration of more than 15 years [3,4]. NMS may escape attention unless specifically interrogated, as demonstrated in a recent hospital-based survey using the Non-Motor Symptom Questionnaire, which identified an average of 11 NMS per patients as opposed to less than five that had been captured in routine case notes of these subjects [5], the most common being nycturia, urgency, memory impairment, constipation and depressed mood. Apart from being common in advanced stages of disease, NMS may be a presenting symptom of PD, preceding the full expression of classical motor signs. A recent study found that 21% of a PD sample had presented in that fashion and NMS presentation was associated with delayed diagnosis [6]. NMS are a significant contributor to overall disability and disease burden, as exemplified by cognitive decline and dementia, which have been associated with a more rapid progression of disability, increased risk for nursing home care and mortality [4] or symptomatic orthostatic hypotension, which is one of the major risk factors of falls in PD [7]. Some studies have found closer correlations with Quality of Life scores of NMS compared with motor symptom rating scores [8].

Treatment of NMS: current challenges

Despite the high prevalence and impact of NMS in PD, there are only few therapies available for which efficacy is sufficiently supported by evidence from randomized controlled trials in PD populations. A recent review of all available clinical trials targeting the NMS of PD found only three agents for which the available evidence suggested that they were at least likely efficacious to treat depressive symptoms (the dopamine agonist pramipexole, and the tricyclics nortriptyline and despiramine, while there was insufficient evidence for efficacy of all selective serotonin reuptake inhibitors tested in PD) [9]. Likewise, the cholinesterase inhibitor rivastigmine was the only agent with robust enough evidence for efficacy to treat PD dementia, while evidence for other drugs of this class like donepezil or galantamine, as well as for memantine was insufficient. Other drugs with sufficient evidence for efficacy to treat NMS in PD included clozapine for psychosis, and botulinum toxin and glycopyrrolate to treat sialorhea [9], while there was insufficient evidence for efficacy of any intervention to treat such common problems like fatigue, orthostatic hypotension, bladder disturbances, erectile dysfunction, insomnia and excessive daytime sleepiness [9]. Much of the routine management of NMS in PD is, therefore, based on pragmatic approaches extrapolating from trial results and clinical experience with similar problems in non-PD populations, and more controlled trials are needed to better define efficacy and safety of interventions to treat NMS in PD. Future perspectives are disease-modifying therapies which may alter the underlying progression of both motor and nonmotor symptoms. To achieve this goal diagnosing patients at the earliest stage of their illness which might be before the full expression of classical motor symptoms, is essential.

NMS & the concept of preclinical PD

Many of the NMS seen in patients with PD seem to be nonspecific in that they also commonly occur in non-Parkinsonian or neurologically normal subjects, including hyposmia, constipation or depression. Intriguingly, recent studies have provided convergent evidence that the presence of such NMS in healthy subjects may confer an increased risk to subsequently develop PD. In a large population-based cohort, hyposmia was associated with a fourfold risk for incident PD over 4 years following the baseline test [10]. Moreover, postmortem brain examination of individuals of the same cohort revealed an association between poor smell function and Lewy body degeneration in the olfactory tract [11]. This would be broadly consistent with the popular hypothesis developed by Braak and colleagues [12] whereby pathology in the olfactory tract would precede neuronal degeneration in the substantia nigra during the evolution of PD [12].

Another intriguing finding from the same cohort has shown a significant increase in the risk for incident PD in subjects with constipation compared with those with at least one bowel movement per day [13]. Strikingly, significantly more subjects with constipation in life had incidental Lewy body degeneration in the substantia nigra at postmortem compared with those with normal bowel movement frequencies [14]. Finally, idiopathic REM sleep behavior disorder (RBD) has been consistently associated with the later development of synuclein, related neurodegenerative diseases such as PD, dementia with Lewy bodies and MSA. Depending on the duration of follow-up between 45 and 65% of the subjects with idiopathic RBD went on to develop one of these neurodegenerative conditions – most commonly, PD [15,16]. This course of events is again broadly consistent with the Braak hypothesis of early neuropathological involvement of the caudal brain stem in PD, prior to involvement of the substantia nigra. These findings have had major implications on current concepts of PD.

As the occurrence of NMS may predate full-blown motor manifestation of PD, there is a need to identify NMS as evidence of PD [2,17]. However, with the possible exception of RBD, all of these NMS are nonspecific and only a minority of individuals with these symptoms will develop PD in their lives.

Nevertheless, an accurate definition of subjects at risk for PD is particularly significant as a window of opportunity for early intervention with potential to slow or even prevent full manifestations of disease. Using NMS as a potential PD risk marker in combination with imaging or molecular biomarkers might be a future way of enriching at-risk cohorts. Preliminary results of the PARS (Parkinson’s disease at risk syndrome) cohort, where a large cohort of healthy subjects was invited to undergo smell testing reveal that hyposmics were more likely to show reduced dopamine transporter binding using single photon emission computed tomography (SPECT) [18]. Similarly, using transcranial ultrasound or dopamine transporter SPECT in subjects with idiopathic RBD was shown to enhance prediction of subsequent PD in a recent study [19].

In summary, for a better understanding of the etiopathogenesis of PD and for the effort to develop more effective disease modifying and eventually even preventive interventions, we must acknowledge that the current definition of PD may no longer be sufficient. A new definition of PD should consider the disease as a multisystem synucleinopathy with pathology extending beyond the borders of the central nervous system and clinical manifestation including a variety of NMS beyond the cardinal motor features. Efforts are underway to define criteria for a new entity of ‘premotor’ PD [17].

Financial & competing interests disclosure

K Seppi has received honoraria from AOP Orphan Pharmaceuticals AG, Boehringer Ingelheim and Lundbeck, and has been awarded grants from Medical University Innsbruck and Oesterreichische Nationalbank. W Poewe has received consultancy and lecture fees from AstraZeneca, Teva, Novartis, GSK, Boehringer Ingelheim, UCB, Orion Pharma, Merck Serono and Solvay-Abbott in relation to clinical drug development programs for PD; has been awarded an AstraZeneca grant (2009–2012); and has received royalties from Oxford University press and Wiley-Blackwell. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.