Non-motor symptoms in Parkinson’s Disease: burden and role in possible prodrome

Parkinson’s Disease (PD) is a multi-system condition involving cognition, the gastrointestinal (GI) tract, pain, sleep, and urinary and sexual dysfunction. James Parkinson himself, in his 1817 Essay on the Shaking Palsy, was well aware of non-motor problems such as pain and constipation. In clinical PD, they represent a major additional burden. In the early, untreated phase of the disease, non-motor symptoms may predominate.

The apparent existence of a prodromal phase characterized by non-motor symptoms may offer opportunities to intervene and so prevent the development of classical Parkinsonism. And the differing patterns of both motor and non-motor symptoms among patients suggest the need for subtyping within PD.

Non-motor problems are strongly associated with poor quality of life

Many sources of complexity

One element of complexity is that the motor phenotypes themselves differ between patients, and change over time. So a patient with an initial presentation dominated by tremor may develop a disease characterized by postural instability, and vice versa.

PD involves the substantia nigra, of course, but also the olfactory bulb and lower brainstem and, ultimately in many patients, the cortex. Olfactory deficits seem to precede motor symptoms by up to twenty years. Cholinergic denervation has been implicated; and degeneration of the forebrain cholinergic system appears early in the disease course.

Acetylcholine seems related to cognitive symptoms, from mild impairment to dementia. Up to 90% of Parkinson’s patients have cholinergic cell loss and 50% loss of serotonergic cells. The latter may relate to depression and fatigue, as well as to dyskinesias.

Levels of noradrenaline are abnormally low in several areas of the brain; and noradrenaline dysregulation can be linked to both autonomic dysfunction and sleep disturbance.

Loss of orexin/hypocretin cells in the brain is associated with sleep problems such as rapid eye movement behaviour disorder – the so-called “spousal arousal” syndrome – and daytime somnolence has been linked to low levels of orexin/hypocretin in ventricular CSF.

Non-motor symptoms are common, severe and heterogeneous. In established disease,  they represent a major unmet need. In the prodrome, their identification offers opportunities for early intervention

Management according to clinical subtypes

The many non-motor domains that can be affected – and there are up to ten of them – have implications for diagnosis, management, and how we conduct clinical trials. Patients differ in the extent of non-motor symptoms, and in the nature of those symptoms. If there are clear subtypes, our management should differ in a corresponding way. One potentially important distinction is between non-motor subtypes with or without cognition deficits.

Subtypes may reflect different neuropathology, with symptoms dominated by cognitive deficits and apathy related particularly to neocortical involvement and patients with prominent sleep abnormalities being more likely to have brainstem pathology. Patients with excessive daytime somnolence show low uptake of serotonergic transporter in the raphe nuclei.

In short, patients have different routes into Parkinsonism.

Non-motor symptoms are common, severe and heterogeneous. In established disease, their treatment is a major unmet need; but the reality is that most existing treatments are licensed solely on the basis of their efficacy against motor symptoms.

Is there a Parkinson’s prodrome?

The 2015 clinical diagnostic criteria of the Movement Disorder Society retain bradykinesia, rest tremor and rigidity as the major symptoms of PD, but they recognise the importance of non-motor aspects of the disease. Non-motor features are regarded as especially important in the development of separate criteria for prodromal PD.

If there is a Parkinson prodrome, the idea – though controversial – might be the chance to intervene many years earlier 

If non-motor symptoms become established as part of a prodromal phase, their identification may offer opportunities for earlier intervention – assuming that we can develop potentially neuroprotective, disease-modifying agents that are well tolerated. The challenge of defining high-risk groups for inclusion in the necessary trials will have to be met using non-invasive biomarkers and clinical features.

The caveat in advocating non-motor symptoms for such a role is that symptoms of the kind discussed are also very common among people who do not have -- and never will have -- PD.

In all this complexity there is, however, one simple fact. Since 65 years is the median age of PD onset, and since the population of the world is growing inexorably older, the number of people with PD is set to double by the year 2030. Finding new ways of tackling this burgeoning problem – and, ideally, preventing it -- becomes increasingly important.