Prodromal Parkinson’s Disease and its Implications for Longitudinal Studies

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by movement abnormalities such as resting tremor, bradykinesia, and rigidity. In addition, non-motor symptoms such as decreased ability to smell, constipation, and sleep disorders are often present years before the clinical diagnosis of PD, also known as the prodromal period. PD affects close to one million Americans and its prevalence is expected to grow as the population ages. Existing treatments are not known to stop or slow the progression of the disease and few potential preventive factors have been proposed. The limited number of preventive factors may be due to the lack of large prospective studies with enough follow-up to enable the assessment of long-term exposures while accounting for the long prodromal phase of PD. In Chapter 1, we used data from 804 men participating in the Health Professionals’ Follow-up Study (HPFS) to describe how experiencing combinations of hyposmia, constipation, and probable REM sleep behavior disorder (pRBD), common non-motor features of prodromal PD, are related to objective and subjective measures of cognitive function. In line with previous investigations, we found that the objective cognitive performance was worse in individuals with prodromal PD features, particularly among those with all 3 features, who are probably in the prodromal phase of PD. These men were also more likely to experience subjective cognitive decline (SCD) than men with no prodromal features encouraging further investigation of this marker. In Chapter 2, we used data from 12,427 women from the Nurses’ Health Study (NHS), to examine whether SCD is more likely to be present in women with features suggestive of prodromal PD, compared to women without these features. Women experiencing the 3 examined non-motor features (hyposmia, constipation and pRBD) had the worst mean SCD score and the highest odds of poor subjective cognition. This association persisted when women with objective cognitive deficits were excluded from analyses. SCD was also more common in women with a probability of prodromal PD ≥0.80, based on the MDS score, particularly among those younger than 70 years. Our study suggests that SCD is common among individuals who are probably in the prodromal phase of PD. Our SCD assessment may be a time- and cost-efficient tool for large-scale screening for prodromal PD, particularly in combination with other prodromal markers and in younger populations. In chapter 3, we leveraged longitudinal data from the NHS and HPFS collected over ~30 years of follow-up and investigated the association between long-term intake of folate, vitamin B6, and vitamin B12 with the subsequent occurrence of PD. We did not observe an association between intake of folate or vitamin B6 and the risk of PD. Results for vitamin B12 suggested a modest inverse association, particularly for baseline intake. Recent intake of folate, B6 and B12 supplements tended to be associated with higher PD risk, a trend consistent with reverse causality. Our study leaves open the possibility of a protective effect of vitamin B12 on the development of PD and highlights the implications of reverse causality when studying risk or protective factors for PD.