Chair: Michał Węgrzynowicz (Mossakowski Medical Research Institute, Warsaw, Poland)

Symposium 4: On the way to Parkinson’s disease: molecular, cellular and clinical aspects of prodromal synucleinopathies

Our current understanding of Parkinson’s and related disorders makes us aware that pathology begins decades before diagnosis and spreads throughout nervous system, progressively affecting new sites. Thorough insight into different aspects of prodromal synucleinopathies will enable to develop diagnostic and therapeutic tools to halt the disease before major symptoms emerge.


Nathalie Van Den Berge, PhD, Aarhus University, Aarhus, Denmark

Prodromal subtypes of synucleinopathies – knowledge from animal models

In synucleinopathies such as Parkinson’s disease (PD), alpha-synuclein (asyn) pathology can propagate along the brain-body axis affecting multiple organs. Patients display highly heterogeneous early disease phases, limiting accurate early diagnosis. Increasing data suggests disease heterogeneity can be explained by variable disease initiation site, as postulated by body-first and brain-first PD subtypes. We aim to model progressive body-to-brain and brain-to-body development of human disease in the gut, heart, skin and brain of old wild-type rodents. We use these models to develop non-motor biomarkers using multi-organ imaging and histology of peripheral biopsies. Our findings greatly deepen our understanding of prodromal PD and early stratification has potential applications in clinical trials and personalized therapeutics.

References:
1. Borghammer P. and Van Den Berge N. Brain-First versus Gut-First Parkinson’s Disease: A Hypothesis. J Parkinsons Dis., 2019. doi: 10.3233/JPD-191721
2. Van Den Berge N, et al. Ageing promotes pathological alpha-synuclein propagation and autonomic dysfunction in wild-type rats. Brain, 2021. doi: 10.1093/brain/awab061


Grzegorz Kreiner, PhD Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Cracow, Poland

Prodromal model of Parkinson’s disease based on targeting noradrenergic system

Parkinson’s disease (PD) is characterized by progressive loss of dopaminergic neurons of substantia nigra (SN) and ventral tegmental area (VTA), directly responsible for symptomatology. However, PD is associated with malfunctions in the noradrenergic system as well. Degeneration of locus ceruleus (LC) in PD patients may even exacerbate the loss of SN/VTA neurons. Recently, we have shown that enhancement of noradrenergic transmission can have beneficial effects in transgenic mouse model of progressive parkinsonism. On the other hand, our newly created mouse model of selective degeneration of LC influenced negatively functioning of the dopaminergic system. These mice may become a valuable tool to study the prodromal phase of PD and neuroprotective therapies.

References:
1. Braak et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging., 2003. doi: 10.1016/s0197-4580(02)00065-9
2. Barut et al. Genetic lesions of the noradrenergic system trigger induction of oxidative stress and inflammation in the ventral midbrain. Neurochem Int., 2022.
doi: 10.1016/j.neuint.2022.105302


Ambra Stefani, MD, PhD, Medical University of Innsbruck, Innsbruck, Austria

Relevance of isolated REM Sleep Behaviour Disorder as prodromal synucleinopathy

Isolated REM sleep behaviour disorder (iRBD) represents an early stage synucleinopathy. Clinical aspects will be presented, as well as challenges in diagnosis and screening with insights into new methods to overcome them. The speaker will also provide an overview of biomarkers in iRBD, addressing different types of biomarkers and their potential role in the context of neuroprotective/neuromodulating trials.

References:
1. Miglis MG, et al. Biomarkers of conversion to α-synucleinopathy in isolated rapid-eye-movement sleep behaviour disorder. Lancet Neurol., 2021. doi: 10.1016/S1474 4422(21)00176-9
2. Högl B, et al. Rapid eye movement sleep behaviour disorder: Past, present, and future. J Sleep Res., 2022. doi: 10.1111/jsr.13612


Giorgio Vivacqua, MD, PhD, Campus Biomedico University of Roma, Rome, Italy

Salivary biomarkers in prodromal synucleinopathies and Parkinson’s Disease

A mismatch between clinical and neuropathological onset of synucleinopathies hampers the efficacy of disease-modifying therapies, calling for pre-clinical molecular diagnosis. Salivary glands are richly innervated by visceral fibres which enter in strict contact with secretory adenomeres, making saliva a source of biomarkers for neurological disorders. Altered salivary biomarkers were found in saliva of patients affected by different synucleinopathies. RT-QuIC assay reveals seeding-competent alpha-synuclein in PD patients saliva and correlates with disease severity. Alterations in autophagic and inflammatory markers enable molecular clustering of PD patients and are observed in iRBD subjects. This makes saliva a key biofluid candidate for diagnosis of prodromal synucleinoapthies and for early discrimination of different clinic-molecular subtypes of PD.

References:
1. De Bartolo MI, et al. A Combined Panel of Salivary Biomarkers in de novo Parkinson’s Disease. Ann Neurol., 2023. doi: 10.1002/ana.26550
2. Vivacqua G, et al. Salivary α-Synuclein RT-QuIC Correlates with Disease Severity in de novo Parkinson’s Disease. Mov Disord., 2023. doi: 10.1002/mds.29246

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