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How to discover prodromal Parkinson's disease and why

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After the discovery of the Lewy Body in 1912, the depigmentation of the substantia nigra in 1919 and the dopamine deficit in 1960 in post mortem brain tissue of PD patients the subsequent i.v. administration of L-Dopa in PD patient in 1961 resulted in a dramatic symptomatic improvement of the cardinal motor signs of PD patients. This therapeutic breakthrough initiated a 40 year long research on how to improve the symptomatic dopamine replacement pharmacotherapy (agonist, MAO B-inhibitor, COMT -inhibitor) in PD. In 1996/7 three discoveries dramatically changed the PD research field: 1) an autosomal-dominant mutation of the alpha-synuclein gene (SNCA) was found to be responsible for a (rare) familiar form of PD. 2) alpha-synuclein aggregates were demonstrated (in Cambridge, UK) in the Lewy bodies and subsequently PD and its variant dementia with Lewy bodies (DLB) – were classified as alpha-synucleinopathies, 3) the parasomnia REM -sleep behaviour disorder (RBD) was reported to be a candidate for a prodromal stage of PD. In 2003 Braak and coworkers published – entirely based on the neuropathological distribution of Lewy bodies in incidental Lewy body brains and PD brain the Braak PD staging. These authors proposed that PD may originate in the periphery (gastrointestinal tract, olfactory system). This hypothesis was challenged and recently the Body first PD versus Brain first PD subtype concept was proposed by Horsager et al 2020.

25 years after the discovery that alpha-synuclein likely plays a major role in the etiopathogenesis of the majority of PD patiens, therapies which target alpha-synuclein overproduction, aggregation or try to enhance alpha-synuclein degradation have entered the clinical trial phase with the hope, that some of them may provide a modification of the progression of manifest PD. A recent survey on clinical trials in PD identified 65 studies testing potentially disease modifying therapies in early (mostly de novo) PD patients. In case one or more of these therapeutic candidates will be demonstrated to slow down or stop the progression of PD, it will be discussed to administer these compounds in the prodromal stages of PD. This later approach would test whether the compound in question allowed to delay or prevent the manifestation of motor signs and syBD, mptoms of PD. Thus it will be essential to identify prodromal stages of PD with reliable biomarkers and even to find progression markers of the prodromal progression of alpha-synucleinopathies. The talk will present recent data on how to diagnose prodromal PD with the focus on REM sleep behaviour disorder (RBD). RBD is now considered as a common, highly specific prodromal stage of PD and DLB . Based on multimodal phenotyping and long term follow-up studies in RBD , modalities like video-assisted polysomnography, screening questionnaires for RBD , tests for olfactory function and speech parameters, imaging for peripheral and central indicators (MIBG scan, DAT SPECT , FDG-PET), biotissue and biofluid parameters will be discussed.

Doppler et al 2017, Postuma et al 2019, Jiang et al 2020, Horsager et al 2020, Doppler et al 2021, Kogan et al 2021, Miglis et al 2021, Perkins et al 2021, Rusz et al 2021

This talk is part of the Biophysical Seminars series.

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