Abstracts

Parkinson’s disease (PD) is the fastest-growing neurological disease characterized clinically by motor dysfunction, cognitive decline and autonomic dysfunction, currently affecting over 7 million patients worldwide. Development of preventative therapies is limited because we insufficiently understand the underlying biology and pathobiology. Furthermore, no reliable biomarker exists that predicts the prognosis and outcome of PD. One reason is the large heterogeneity in underlying etiology, pathophysiology and clinical presentation that is typical of PD, with unique profiles for each patient. An accurate and early as possible diagnosis is crucial for the development of novel disease-modifying therapies of PD. For, this goal we study molecular biomarkers in body fluids, mainly cerebrospinal fluid, for early identification of PD. I will discuss the most important emerging molecular biomarkers for PD.

Despite advances in diagnostic procedures, differentiating between PD and several atypical Parkinsonisms (AP) remains a major challenge, especially early in the disease course. MSA is the largest subgroup among the various forms of AP, a group that initially present as PD, but typically follows a more malignant disease course than PD. Moreover, unlike PD, people with AP do not respond well to dopaminergic therapy. Since the clinical diagnostic accuracy is often very low at the time of the initial diagnosis (when the diagnosis cannot yet be established based on the clinical presentation alone), molecular biomarkers that discriminate between PD and AP are dearly needed. I will also discuss developments in this area of research.

Finally, many persons with PD (estimated at 25-55%) develop small intestinal bacterial overgrowth (SIBO) which negatively affects their quality of life by causing abdominal pains, constipation, bloating, nausea, diarrhea and excessive flatulation. Moreover, SIBO has also been associated with the occurrence of response fluctuations and longer ‘off—time’ during use of oral levodopa medication, likely because of changes in gut microbial composition which interferes with levodopa metabolism. I will also discuss our research on the role of the gut microbiome in determining the response to levodopa, which currently remains the therapeutic cornerstone for people with PD.

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Abnormal assembly of tau, α-synuclein, TDP-43 and amyloid-β proteins into amyloid filaments defines most human neurodegenerative diseases. Genetics provides a direct link between filament formation and the causes of disease. Developments in cryo-electron microscopy (cryo-EM) have made it possible to determine the atomic structures of amyloids from postmortem human brains. In my lecture, I will introduce the cryo-EM technique to calculate atomic structures, I will review the structures of brain-derived amyloid filaments that have been determined so far and I will discuss their impact on research into neurodegeneration. Whereas a given protein can adopt many different filament structures, specific amyloid folds define distinct diseases. Amyloid structures thus provide a description of neuropathology at the atomic level and a basis for studying disease. Future research should focus on model systems that replicate the structures observed in disease to better understand the molecular mechanisms of disease and develop improved diagnostics and therapies.