Range of Risk Factors, Comorbidities, and Prodromal Features Identified Prior to Parkinson Disease

Subsequent diagnosis of Parkinson disease was associated with a range of risk factors such as alcohol misuse and traumatic head injury, along with several other comorbidities and prodromal features.

Anette Schrag, MD, PhD, professor of clinical neurosciences, UCL Queen Square Institute of Neurology

Anette Schrag, MD, PhD

Findings from a case-control study using insurance claims of outpatient consultations highlighted several previously known early features associated with subsequent diagnosis of Parkinson disease (PD). These associations may reflect possible early extrastriatal and extracerebral pathology of the disease because of shared risk with PD, medication exposure, or direct causation, or represent pathophysiologically relevant factors contributing to the pathogenesis of PD.

Lead investigator Anette Schrag, MD, PhD, professor of clinical neurosciences, UCL Queen Square Institute of Neurology, and colleagues identified a total of 138,345 patients with incident PD without a diagnosis of parkinsonism or dementia and matched them 1:2 with 276,690 controls. Using data on patients from 2011 to 2020, the analysis only included prodromal features, risk factors, and comorbidities coded by general practitioners.

The mean follow-up time for both cases and controls was 6 (standard deviation [SD], 2) years. Almost two-thirds (74%) of patients with PD and 10% of controls were examined by a neurologist during the insurance quarter of diagnosis. In terms of suspected prodromal presentations, several were linked to subsequent diagnosis of PD, including motor features of tremor (odds ratio [OR], 11.38; 95% CI, 10.51-12.32), gait impairment (OR, 1.90; 95% CI, 1.83-1.98), stiffness of joints (OR, 1.32; 95% CI, 1.17-1.50), shoulder pain (OR, 1.15; 95% CI, 1.06-1.24), and neck pain (OR, 1.16; 95% CI, 1.12-1.20).

The autonomic presentations of dizziness (OR, 1.60; 95% CI, 1.55-1.66), postural hypotension (OR, 1.40; 95% CI, 1.32-1.49), constipation (OR, 1.84; 95% CI, 1.76-1.93), features of sexual dysfunction (OR, 1.20; 95% CI, 1.11-1.30), and neurogenic bladder (OR, 1.72; 95% CI, 1.52-1.94) also revealed positive associations with a diagnosis of PD. Additionally, several other features showed associations, including fatigue ((OR, 1.43; 95% CI, 1.37-1.50); the neuropsychiatric presentations of depression (OR, 1.86; 95% CI, 1.81-1.92), anxiety (OR, 1.65; 95% CI, 1.57-1.74), and memory problems (OR, 1.72; 95% CI, 1.59-1.85); the sleep disorders of restless leg syndrome (OR, 4.19; 95% CI, 3.91-4.50), parasomnias (including RBD; OR, 1.62; 95% CI, 1.42-1.84), sleep apnea (OR, 1.45; 95% CI, 1.37-1.54), insomnia (OR, 1.40; 95% C,I 1.31-1.49), other sleep disorders (OR, 1.41; 95% CI, 1.35-1.47).

Although rare, hypersomnia (OR, 2.16; 95% CI, 1.27-3.68) was also positively associated with subsequent diagnosis of PD. Schrag et al wrote, “Consistent with previous reports, we found associations with neuropsychiatric features of early and prodromal PD, including depression and less commonly, anxiety, notably even in the earliest prediagnostic period. Interestingly, these neuropsychiatric features included memory complaints even more than 5 years before diagnosis, albeit much less commonly than depression or anxiety. Among the autonomic features, dizziness was present in more than 10% of patients more than 5 years before diagnosis of PD.”

In terms of sensory changes, anosmia (OR, 2.16; 95% CI, 1.59-2.93), hearing loss (OR, 1.14; 95% CI, 1.09-1.20), alterations in skin sensation (OR, 1.31; 95% CI, 1.21-1.43), nonspecific pain (OR, 1.13; 95% CI, 1.09-1.17), and subjective visual disturbance (OR, 1.26; 95% CI, 1.01-1.57) and for diagnoses of the skin conditions seborrheic dermatitis (OR, 1.30; 95% CI, 1.15-1.46), psoriasis (OR, 1.13; 95% CI, 1.05-1.21), and dermatophytosis (OR, 1.25; 95% CI, 1.19-1.32), were all positively associated with PD diagnosis.

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Preceding alcohol misuse (OR, 1.32; 95% CI, 1.21-1.44) and traumatic brain injury (OR, 1.62; 95% CI, 1.36-1.92) as well as for hypertension (OR, 1.29; 95% CI, 1.26-1.31) and hypercholesterinemia (OR, 1.11; 95% CI, 1.08-1.13) were all suspected risk factors with an increased OR for subsequent PD diagnosis. Notably, investigators found a reduced OR for nicotine misuse (OR, 0.92; 95% CI, 0.86-0.98) with PD. Those with diabetes type 1 (OR, 1.32; 95% CI, 1.21-1.43) and type 2 (OR, 1.24; 95% CI, 1.20-1.27) were associated with subsequent diagnosis of PD overall and in all time periods before receiving diagnosis.

Several comorbidities, including diagnoses of schizophrenia (OR, 4.48; 95% CI, 3.82-.5.25) and bipolar disorder (OR, 3.81; 95% CI, 3.11-4.67) were associated with increased risk for PD diagnosis. There was also an increased OR for the gastrointestinal comorbidities of gastroesophageal reflux disease (OR, 1.29; 95% CI, 1.25-1.33), gastritis (OR, 1.28; 95% CI, 1.24-1.33), and gastric ulcer (OR, 1.24; 95% CI, 1.12-1.37), with less-consistent associations over time periods for duodenal ulcer (OR, 1.13; 95% CI, 1.00-1.29), Crohn disease (OR, 1.21; 95% CI, 0.99-1.48), and ulcerative colitis (OR, 1.23; 95% CI, 1.06-1.43). Notably, although rare, there were no significant association for cytomegaloviral disease and infectious mononucleosis.

REFERENCE
Schrag A, Bohlken J, Dammertz L, et al. Widening the sprectrum of risk factors, comorbidities, and prodromal features of Parkinson disease. JAMA Neurol. Published online November 7, 2022. doi:10.1001/jamaneurol.2022.3902
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