In a classic paper based on the detailed assessment of 216 people with PD, Gilles Fénelon and colleagues found that 40% had experienced hallucinations – visual in the majority of cases – in the previous three months.10 The authors suggested that this high prevalence could not be explained solely as a side effect of chronic dopaminergic treatment: hallucinations can occur in newly diagnosed patients; and cognitive impairment and disturbances in the sleep-wake cycle were identified as important factors.
In a recent review, Goldman and Holden drew attention to adverse effects of both psychosis and dementia on the quality of life of PD sufferers and caregivers alike.9 The authors estimate that the prevalence of psychosis in PD is probably over 50%, and emphasize that psychosis and dementia are interlinked phenomena associated with increased need for nursing home placement and higher rates of morbidity and mortality. In 2018, Mahlknecht et al reported a 52% rate of hallucinations or delusions among a control group of PD patients followed for ten years in a study of deep brain stimulation.15 This provides support for the view that the lifetime prevalence of psychosis in PD is indeed around 50%.
Genetic and other factors related to the risk of early PD-related psychosis are being identified. There appear to be racial or ethnic differences in susceptibility to hallucinations; and evidence for the involvement of cortical thinning is intriguing.16
Cognitive impairment in people with PD often has a profoundly adverse effect on their carers
Progressive cognitive impairment affecting a wide range of domains is frequent7 and has recently been described as the most significant NMS associated with PD.1 Figure 2 provides details of the impact of cognitive dysfunction on those who care for people with PD. Cognitive deficits have been reported even in prodromal PD, and up to 80% of patients with a long history of the disease are thought to develop dementia. It has been estimated that 10% of people with PD develop the condition each year.9
The principal pathology is the diffuse presence of cortical Lewy bodies.1 The range of neurotransmitters involved in PD-associated cognitive impairment includes acetylcholine and norepinephrine, as well as dopamine. Glucocebrosidase (GBA) polymorphisms and mutations have recently been linked to increased risk of PD dementia.17
Both disorders are likely to be due to a complex interplay between neurobiological factors and the psychological consequences of having a chronic, degenerative disease.18 In the case of depression, the former are said to include abnormalties of basotemporal limbic circuitry and a range of neurotransmitters such as norepinephrine, serotonin and dopamine.
Lewy bodies are frequently found in the autonomic nervous system of people who die with PD, and autonomic dysfunction in various forms is a common part of PD symptomatology.19 Autonomic problems may become apparent in erectile and urinary dysfunction, for example. But these conditions are so closely related to age that it is not straightforward to disentangle the role of PD. However, the association of PD with gastrointestinal dysfunction – aspects of which may precede the onset of motor symptoms by many years – is both clear and intriguing.
Radiotracer and imaging studies have shown extensive pathology of the sympathetic and parasympathetic nervous systems in people with PD.14 Disordered pharyngeal and esophageal motility is frequently evident, along with delayed gastric emptying and colonic transit. Chaudhuri et al recently cited an estimate that more than 70% PD patients have GI disorders.5 These include gastric dysmotility and small intestinal bacterial overgrowth. In addition to the associated morbidity, gastroparesis has implications for the delayed absorption of oral drugs, notably levodopa.
A history of constipation is associated with an increased risk of PD, preceding diagnosis significantly more frequently in those who develop the disease than in matched controls.19,20
The autonomic dysfunction associated with synucleinopathies can prevent sufficient compensatory release of norepinephrine from sympathetic nerves, leading to hypotension on standing.21 In a study from Baylor College of Medicine, orthostatic hypotension was found in 18% of people with PD and its occurrence was associated with greater age, longer duration of parkinsonian symptoms, and more advanced Hoehn and Yahr stage.22
Lim and Lang recently considered whether orthostatic hypotension is intrinsic to PD or caused predominantly by treatment.11 They concluded that evidence of reflexive cardiovagal failure, sympathetic neurocirculatory failure and extracardiac noradrenergic denervation in a substantial proportion of untreated PD patients suggests it is part of the underlying disease process.
Orthostatic hypotension has significant effects on quality of life since falls and the fear of falls limit social and physical activity, and cardiac decompensation can lead to disability. In recognition of the importance of this problem, the American Autonomic Society and the National Parkinson Foundation recently issued joint recommendations on screening for orthostatic hypotension and its management.21
Idiopathic REM sleep behavior disorder looks like a very early manifestation of synucleinopathy
The majority of people with idiopathic REM sleep behavior disorder (RBD), characterized by a loss of atonia which allows complex motor behaviors including the acting out of dreams, will eventually be diagnosed with PD or a related synucleinopathy.23 St Louis et al cite a range of 40-90% among longitudinal series of RBD patients followed for six years or longer.
As a prodromal feature, RBD probably has the greatest predictive power of the non-motor symptoms associated with PD. Also striking is the length of time by which the disorder can precede PD, which may not be diagnosed for several decades after the sleep problem becomes apparent.24
Estimating the prevalence of RBD in established PD is made difficult by differences in definition. However, a recent estimate suggests it is in the region of 25-30% in newly diagnosed patients and those with early disease.25
The view that RBD is early evidence of a widespread underlying synucleinopathy is supported by its association with other markers of neurodegeneration such as cognitive impairment, constipation, orthostatic hypotension, and hyposmia.23
Disorders of smell are another NMS closely associated with PD and predictive of its development. Doty estimates that around 90% of people with early PD experience olfactory dysfunction.26 This symptom is shared with many Alzheimer’s Disease patients, but is not as apparent in multiple system atrophy and progressive supranuclear palsy, making loss of smell potentially valuable as a means of distinguishing between parkinsonian syndromes. Hyposmia is also an NMS associated with diminished quality of life: among 750 consecutive patients attending a University of Pennsylvania smell and taste clinic, more than half reported adverse effects on psychological wellbeing.26
Up to 90% of people with early PD suffer loss of smell
While the new Movement Disorder Society Clinical Diagnostic Criteria retain bradykinesia plus rest tremor or rigidity as the core features of parkinsonism, they give new emphasis to non-motor aspects of the disease.28 This is intended to better reflect current understanding and diagnostic practice in expert centers.
Once parkinsonism has been documented, the judgement that PD is the cause relies on three categories of diagnostic features:
- absolute exclusion criteria, which rule out PD (dementia has now been removed as an exclusion criterion for PD, even if it is the first presenting symptom)
- red flags, which must be counterbalanced by additional supportive criteria to allow diagnosis of PD, and
- supportive criteria ie positive features that increase confidence in the PD diagnosis.
Loss of olfaction is one such supportive feature. The other side of the coin is that absence of any common NMS (despite at least five years’ disease duration) is regarded as a red flag. The relevant NMS include RBD, constipation, symptomatic orthostasis, and psychiatric dysfunction (depression, anxiety or hallucinations).
Non-motor features were regarded as especially important in the development of the MDS’s companion set of criteria for prodromal PD.29 These criteria are intended at least initially for use in a research context but acknowledge that PD pathology and related symptoms involve the peripheral nervous system and non-dopaminergic brain structures. The likelihood of prodromal PD is calculated based on age, environmental and genetic risk factors, biomarkers (eg dopaminergic imaging) and prodromal symptoms and signs such as constipation and hyposmia.