Abstract Body

Although the diagnosis of Parkinson’s disease (PD) relies on the clinical effects of dopamine deficiency, this disease is associated with other neurotransmitter deficits that cause various motor and non-motor symptoms. Non-motor features may begin with an earlier pre-motor prodrome. The majority of non-motor features are not related to dopaminergic cell loss. Hyposmia, rapid eye movement sleep behavior disorder (RBD), depression, and constipation can precede the symptoms related to dopamine deficiency. Hyposmia is usually bilateral. The development of hyposmia may reflect the evolving distribution and spread of Lewy bodies from the lower medulla, as described by Braak and colleagues. Lewy bodies and Lewy neurites were found in the olfactory bulb, the olfactory cortex, and other brain regions related to olfaction (including the amygdala) in PD but rarely in healthy controls. Dysfunction occurs also in the gastrointestinal tract and includes excessive salivation, dysphagia, impaired gastric emptying, constipation, and impaired defecation. Change in the dorsal motor nucleus of the vagus, in the enteric nervous system, the presence of α-synuclein aggregations along the gastrointestinal tract, occurs early in the development of PD and could explain why gastrointestinal disturbances such as constipation may also occur. Depression in PD may predate the onset of motor symptoms and may associate with noradrenergic function. Patients exhibit reductions in dopaminergic and noradrenergic innervation in the locus ceruleus, thalamus, and limbic brain regions and increases in neuronal loss and gliosis in the locus ceruleus. RBD is a prodromal symptom of PD and has been associated with lower cardiac ¹²³I MIBG uptake.

Abstract Body

Pathogenic mutations in several genes (such as SNCA, LRRK2, PRKN, PINK1, DJ-1 and GBA) have been identified in familial Parkinson’s disease (PD) and more than 90 gene loci have been associated with sporadic PD risk. These discoveries have made important contributions in diagnosis and disease association, and provided some clues underlying the pathophysiology of the disease.

The clinical translational potential of these genetic discoveries have been debated. Will these genetic discoveries lead to a cure or therapies that will prevent or slow down the disease?

Currently, research on the proteins encoded by disease causing genes such as SNCA, LRRK2 and GBA, among others, have provide promising evidence that these targets could lead to neuroprotective therapies.

This lecture will summarise genetic discoveries in PD, highlight it role in clinical diagnosis, its potential in risk prediction, and stratifying patients for neuroprotective trials and for precision medicine. In addition, experimental evidence of the therapeutic potential and clinical trials of genetic targets will be discussed.

Abstract Body

Over the last two decades a substantial progress has been made in understanding of Parkinson’s disease biology and natural history. Most relevantly, the syndrome of premotor (prodromal) manifestations (hyposmia, REM behavior disorder, sleep, autonomic dysfunction among the others) and genetic risk factors have been well defined. On the other hand, not a single disease modifying trial had a positive effect on disease progression despite multiple trials. One of the potential explanations of the recent failures is late timing of intervention as newly diagnosed PD is already associated with significant loss of dopaminergic and other neurons. Constellation of recent failures and better understanding of the scope and natural course of prodromal phase of the disease pave the way to disease prevention studies. Such studies will target prodromal population and test efficacy of intervention to prevent pphenoconversion to clinically defined alpha- synucleinopathy. In order to plan such studies, we need to define the population (WHO), intervention (WHAT) and finally how to measure success (HOW). While a number of observational studies have provided substantial data on the risk of pheconversion in prodromal cohorts to clinically defined a-synucleinopathy, still the challenges remain. An essential aspect of readiness for disease prevention studies is a number of ethical and feasibility considerations of testing interventions in prodromal at-risk participants who do not have disability or clinically defined disease.

This presentation will review the state of the field in regard to readiness for PD prevention studies and outline future directions