These associations may reflect possible early extrastriatal and extracerebral pathology of PD. Risk factors due to shared genetic risk with PD, medication exposure, or direct causation; or may represent pathophysiologically relevant factors contributing to the pathogenesis of PD.
The prodromal phase of PD may last for more than 10 years. Recognition of the spectrum and occurrence of risk factors, comorbidities, and prodromal features of PD can increase understanding of the causes and development of the disease and help identify individuals at risk. A total of 138 345 patients with incident PD (mean age, 75 years); 53% male and 276 690 matched controls were identified. Study participants were followed up for a mean (SD) of six (two) years. Consistent with previous reports, risk factors and prodromal features associated with PD included traumatic brain injury, alcohol misuse, hypertension, anosmia, and parasomnias (including rapid eye movement sleep behaviour disorder). In addition, there were associations with restless legs syndrome, sleep apnoea, epilepsy, migraine, bipolar disorder and schizophrenia. Sensory impairments beyond anosmia, such as hearing loss and changes of skin sensation were also found to be associated with PD.
There were also positive associations with skin disorders (eg seborrheic dermatitis, psoriasis), gastrointestinal disorders (eg gastroesophageal reflux, gastritis), conditions with a potential inflammatory component (eg seronegative osteoarthritis and diabetes types 1 and 2). Associations even five to 10 years before diagnosis included tremor, restless legs syndrome, bipolar disorder and schizophrenia.
Conclusions and Relevance
Results of this case-control study suggest that the associations found between PD and certain risk factors, comorbidities, and prodromal symptoms in a representative population may reflect possible early extrastriatal and extracerebral pathology of PD. This may be due to shared genetic risk with PD, medication exposure, or direct causation, or represent pathophysiologically relevant factors contributing to the pathogenesis of PD.
Schrag A, Bohlken J, Dammertz L, et al. Widening the Spectrum of Risk Factors, Comorbidities, and Prodromal Features of Parkinson Disease. JAMA Neurol. 2023;80(2):161–171. doi:10.1001/jamaneurol.2022.3902