Keynote Presentation: Wide-Spread Unappreciated Alpha-Synuclein Aggregates in CNS - a Cause of Symptoms, Caution and Optimism in Parkinson's Disease and Lewy Body Dementia? With Live Q&A

Parkinson’s disease (PD) belongs the group of synucleinopathies characterized by progressive aggregation of the neuronal protein alpha-synuclein (asyn). Diagnosis and evidence of disease pathology in tissue rely on the demonstration of loss of dopaminergic neurons in substantia nigra, pars compacta and the presence of Lewy bodies in some of the remaining neurons. Lewy bodies are intraneuronal inclusions rich in aggregated asyn. Lewy-like inclusions (Lewy bodies in cell bodies, and Lewy neurites in axons) represents the appreciated pathology in PD and dementia with Lewy bodies. Such inclusions are also used as a marker of asyn pathology in cell and animal models. The patients typically suffer from a range of non-motor symptoms the become worse during the disease. Recent data demonstrates that wider areas of the nervous system is affected by the presence of asyn aggregates than what can be appreciated by immunohistochemical staining of Lewy bodies, and such aggregates can also be detected in biofluids. This less appreciated asyn aggregates tells us that PD initiates long before diagnosis and impact the nervous tissue on a larger anatomical scale than anticipated from the presence of LB. The nature of these non-LB aggregates is still unknown, like their pathophysiological impact but they have contributed to the newly proposed biological staging systems for PD and Lewy body dementia. Their presence in apparently unaffected neurons suggests they are strongly toxic but may contribute to symptomatology by making neuronal circuitries dysfunctional. This opens for new potential symptomatic treatments and disease modifying strategies.

Learning Objectives: 

1. Discuss different hypotheses for the development and progression of Parkinson’s disease.

2. Explain what neuropathology represents the established criteria for diagnosing Parkinson’s disease and their limitation.

3. Discuss the basis for novel analyses that demonstrated alpha-synuclein aggregates in tissue and biofluids that cannot be detected by the standard techniques used to demonstrate the established alpha-synuclein pathology.