Prioritized research recommendations from the National Institute of Neurological Disorders and Stroke Parkinson'sDisease 2014 conference

Parkinson disease (PD) is a serious and rapidly growing public health threat that ranks 24th among all causes of death in the United States. More concerning, PD is the second-fastest increasing cause of US deaths. Most concerning, continued success in limiting the impact of infectious diseases in the developing world is shifting the burden to noncommunicable diseases, with an expected dramatic rise in global PD in the coming generation of older adults. Characteristic motor impairments and brainstem Lewy bodies (LBs) are the classic features of PD. In part because of interventions that effectively mitigate motor symptoms, there is heightened interest in debilitating, nonmotor symptoms of PD, including cognitive impairment, sleep disturbance, neuropsychiatric changes, and autonomic dysfunction that precede motor symptoms in many individuals. PD is a chronic illness that likely begins years prior to full clinical expression; this preclinical period may include a latent stage with no signs or symptoms and a prodromal stage with limited expression of motor and/or nonmotor symptoms. Our understanding of PD has grown to reveal substantial medical complexity. Other parkinsonian conditions, such as multiple system atrophy, can closely mimic PD, especially early in its course. In addition, LBs accumulate beyond the brainstem, including the autonomic nervous system, gut, salivary glands, and skin, raising the possibility that PD may be viewed more accurately as a systemic illness that prominently manifests as a neurodegenerative disease. Finally, pathologic changes of PD can exist alongside Alzheimer disease and vascular brain injury, especially in older individuals, and this confounds diagnosis, clinical management, and research. Medical complexity is further compounded by biological heterogeneity. Knowledge of genetic risk for motor and nonmotor symptoms has advanced greatly and led to the identification of more than 2 dozen independent genetic loci, their products, and the cellular processes that they support; prominent among these are the genes for a-synuclein, DJ-1, LRRK2, PINK1, parkin, and glucocerebrosidase, and the processes of synaptic transmission, mitochondrial function, autophagy, and neuroinflammation. PD likely derives from multiple molecular drivers that vary among individuals, act over years prior to clinical expression, underlie an individual’s ensemble of motor and nonmotor symptoms, and likely dictate response to treatment and its complications. Dopamine replacement therapy and deep brain stimulation (DBS) are seminal advances in PD health care that are the fruits of previous research; however, they have limitations. These interventions appear neither to slow substantially the progress of underlying disease nor to have major impact on nonmotor symptoms; rather, they act mostly to alleviate motor symptoms, sometimes with disabling side effects. Appreciating the tremendous achievements made in bringing these treatments to clinic, the community of investigators focused on PD now strives to develop precision medicine to bring greater clarity to the medical and biological complexity of PD. Key components of this vision of precision medicine include: illuminating fully the overall risk architecture for PD; discovering the molecular mechanisms of disease initiation and progression; developing tools for accurate and early evaluation of disease processes; and implementing safe, effective, and individually tailored interventions with minimal complications. Recognizing that solutions require further research, the National Institute of Neurological Disorders and Stroke (NINDS), in accordance with the Morris K. Udall Parkinson’s Disease Research Act (P.L. 105-78), convened Parkinson’s Disease 2014: Advancing Research, Improving Lives to build consensus on priorities in PD research with participation from >600 patients, caregivers, representatives from nongovernmental and nonprofit groups focused on PD, other stakeholders, and researchers in academia, government, and industry from across North America and Europe. Our efforts began with a request for information that solicited broad community input on scientific opportunities and outstanding needs for research and