Age-related selection bias in Parkinson's disease research: are we recruiting the right participants?

OBJECTIVE: To describe, and explore heterogeneity in, age at onset/diagnosis in Parkinson's disease (PD) and compare mean age at onset/diagnosis in incidence studies with that in general PD research studies. METHODS: We systematically reviewed studies of PD incidence. We meta-analysed mean age at onset/diagnosis and age-stratum-specific incidence rates. We compared age-specific incidence rates in screening studies in the elderly with whole-population studies. We collated mean ages at onset/diagnosis in clinical studies of PD in five journals July-December 2016. RESULTS: In 17 studies reporting sufficient data to pool, mean age at onset/diagnosis was 69.6 years (95% CI 68.2-71.1), but heterogeneity was high (I2 = 96%). In ten of these studies reporting age at diagnosis specifically, the pooled mean age at diagnosis was slightly higher (71.6 [95% CI 70.6-72.6]) with lower, but still high, heterogeneity (I2 = 84%). In twelve whole-population studies reporting age-specific incidence rates, these peaked in age 70-79 (pooled incidence rate per 100,000 = 93.8 [95% CI 80.3-107.4]). Heterogeneity increased with each increase in age stratum (0% in youngest to 88% in oldest age stratum). Pooled age-specific incidence rates in five population-based screening studies of older age groups were several-fold higher than in whole-population studies. The mean of the reported mean ages at onset/diagnosis in recently published research studies was 60.8 (SD 5.6). CONCLUSION: The mean age of onset/diagnosis PD is about 70, although this may be an underestimate due to under-diagnosis in the elderly. Many published studies use age-unrepresentative subjects: the effect of this selection bias deserves further study.

A behaviorally related developmental switch in nitrergic modulation of locomotor rhythmogenesis in larval Xenopus tadpoles.

Locomotor control requires functional flexibility to support an animal's full behavioral repertoire. This flexibility is partly endowed by neuromodulators, allowing neural networks to generate a range of motor output configurations. In hatchling Xenopus tadpoles, before the onset of free-swimming behavior, the gaseous modulator nitric oxide (NO) inhibits locomotor output, shortening swim episodes and decreasing swim cycle frequency. While populations of nitrergic neurons are already present in the tadpole's brain stem at hatching, neurons positive for the NO-synthetic enzyme, NO synthase, subsequently appear in the spinal cord, suggesting additional as yet unidentified roles for NO during larval development. Here, we first describe the expression of locomotor behavior during the animal's change from an early sessile to a later free-swimming lifestyle and then compare the effects of NO throughout tadpole development. We identify a discrete switch in nitrergic modulation from net inhibition to overall excitation, coincident with the transition to free-swimming locomotion. Additionally, we show in isolated brain stem-spinal cord preparations of older larvae that NO's excitatory effects are manifested as an increase in the probability of spontaneous swim episode occurrence, as found previously for the neurotransmitter dopamine, but that these effects are mediated within the brain stem. Moreover, while the effects of NO and dopamine are similar, the two modulators act in parallel rather than NO operating serially by modulating dopaminergic signaling. Finally, NO's activation of neurons in the brain stem also leads to the release of NO in the spinal cord that subsequently contributes to NO's facilitation of swimming.