Summary
The results suggest that there is a strong association between anxiety and later diagnosis of PD in patients aged >50 years who present with a new diagnosis of anxiety. In people with anxiety, the study confirmed that depression, sleep disturbance, fatigue, cognitive impairment, hypotension, tremor, rigidity, balance impairment, and constipation are risk factors for developing PD.
Strengths and limitations
This study used a large electronic health record database that is broadly representative of the UK population. Important factors such as socioeconomic status, lifestyle factors, and confounding conditions, such as severe mental illness, were also included and these results therefore add to what is already known in this area. However, the results are limited by the information entered in the medical records by healthcare professionals, which is primarily added for clinical purposes and not research. Mental health is under-recorded in electronic health records including in older people,17,18 in part because of stigma and negative media portrayal.19 It is therefore possible that the true impact of anxiety on subsequent PD incidence is therefore not fully captured in these results because of under-reporting and under-recording.
Comparison with existing literature
The current findings are in line with results from previous studies reporting an increased risk of PD in people with previous anxiety (HR 1.38, 95% CI = 1.26 to 1.51; HR 1.5, 95% CI = 1.0 to 2.1; and HR 1.63, 95% CI = 1.16 to 2.27)8–10 in a population that is broadly representative of the UK population, even when adjusting for socioeconomic factors, lifestyle factors, and confounding conditions, such as severe mental illness, head trauma, and dementia. It was important to include these conditions as they have been shown to be associated with both anxiety and PD.20–31 Of note, smoking has consistently been negatively associated with PD, whereas it has been positively associated with anxiety. In this study in patients with anxiety, smoking status was not associated with PD when alcohol use and BMI was also accounted for.
In keeping with PD overall, older people, those in a less deprived socioeconomic group, and male individuals with anxiety were at greater risk of a diagnosis of PD. This is similar to the general population, as incidence of a PD diagnosis is known to be higher in older people, males, and those from higher socioeconomic groups.32,33 Anxiety, on the other hand, is more common in females and tends to start earlier in life.34 Primary care doctors under-record anxiety symptoms and diagnoses, sometimes because they do not want to give patients a mental health label.18 It is therefore possible that only more severe forms of anxiety were recorded.
The pattern of clinical features associated with later PD was similar to that reported in the general population previously, including motor features (tremor, rigidity, and balance impairment), autonomic features (constipation and hypotension), sleep disturbance, cognitive impairment, and fatigue.35,36 However, the previously reported features that were not associated with an increased risk of PD in the current study were erectile dysfunction, urinary dysfunction, dizziness, and shoulder pain. This may be owing to these symptoms masking an association of specific presentations such as postural hypotension with later diagnosis of PD or owing to under-reporting of these symptoms in general practice. However, as they were previously shown to be associated with later diagnosis of PD in a similar study design,35 it may also suggest that patients with PD who present with initial anxiety have a specific clinical phenotype with fewer autonomic features. It has been suggested that PD can begin with different phenotypes, reflecting differences in progression pathways.
The condition has been divided using subtyping systems, including according to age-at-onset categories, motor phenotypes, and by non-motor symptoms,37 for example, the neuropsychiatric subtype, where defining symptoms are anxiety and depression, postural instability, and gait disturbances.38,39 There are also subtypes according to whether symptoms do or do not start in the brain (brain- and body-first subtypes).40 There is increasing evidence for specific non-motor dominant PD phenotypes and subtyping may help guide research and clinical practice, although this may be challenging as PD is highly heterogeneous and subtypes are likely to overlap.41 One specific hypothesis suggests that there is a ‘brain-first’ subtype of PD that starts in the brain and spreads to the peripheral autonomic nervous system, and a ‘body-first’ PD pathology that starts in the enteric or peripheral autonomic nervous system and spreads to the brain,40 leading to presentations with orthostatic hypotension, constipation, and olfactory symptoms.42 Onset of PD with anxiety as first presentation may fit into this model of the ‘brain-first’ subtype, with less involvement of peripheral autonomic structures and greater involvement of serotonergic structures involved in early stages.43 Other features of PD that are thought to be related to serotonergic deficits include fatigue, poor sleep, and depression,44 which the study also found to be associated with an increased risk of later PD.
Implications for research and practice
Anxiety is not as well researched as other prodromal features of PD, such as depression. Further research should explore anxiety in relation to other prodromal symptoms and how this symptom complex is associated with the incidence of PD. This may lead to earlier diagnosis and better management of PD. It could also explore if incidence is affected by severity of anxiety, and the authors of the current study recommend that further studies are needed to explore why there is an increased risk of PD in people with anxiety aged ≥50 years.
In conclusion, there was a two-fold increase in risk of PD in patients with first presentation of anxiety aged >50 years. The clinical features of those who developed PD can help identify patients presenting with anxiety who are in the prodromal phase of PD.
