Despite decades of Parkinson’s disease (PD) research, there is still no cure, and patients are often diagnosed when it is too late to intervene. Why is that? Well, you may know PD as a disease of the brain causing the typical motor symptoms. But in fact, the alpha-synuclein pathology, a pathological hallmark of PD, is able to travel along the gut-brain axis, affecting multiple organs along the way and causing a wide range of non-motor symptoms as well. These non-motor symptoms can occur up to 20 years prior to the diagnosis, creating a large pre-motor therapeutic window with opportunity to intervene. That is, if we would be able to identify disease before it has destroyed the brain. However, over 99% of studies focus on modeling disease in the brain only, disregarding the involvement of other organs and the pre-motor phase with non-motor symptoms. This suboptimal disease modeling may have hampered our progress to finding a cure and improved diagnosis.

My group aims to develop comprehensive PD animal models with inclusion of old age, as well as peripheral alpha-synuclein pathology and peripheral nervous system dysfunction, as it occurs in human PD. Recent evidence indicates the existence of two PD subtypes: a body-first and a brain-first subtype. It appears that the place where the very first pathology arises, which can either be in the body (usually the gut), or in the brain, determines the sequence of affected organs and associated symptoms. As the name indicates, the peripheral organs are affected prior to the brain in the body-first type, and the opposite occurs in the brain-first subtype. We model these PD subtypes by initiating disease either in the gut, or in the brain and, by characterizing disease progression in different organs in the pre-motor phase. Besides the classic investigation tools such as histology and behavioral testing, we perform medical imaging and aim to characterize subtype-specific differences in the pathology derived from skin and gut biopsies. This combination of methods enables early identification and longitudinal follow-up of PD subtypes. Our results provide evidence for a subtype-specific sequence of organ involvement in body- and brain-first PD, with earlier cardiac denervation, gut dysfunction and peripheral pathology in body-first PD. Furthermore, we observe subtype-specific morphological differences in alpha-synuclein pathology between subtypes, indicating that the initial location and morphology of the alpha-synuclein pathology are interdependent determinants of the clinical representation of these subtypes.

Despite aging being the main risk factor for developing idiopathic PD, most studies employ young animals in preclinical PD research. However, it has been shown by us and others that aged animals are more susceptible to developing pathology and neurodegeneration. Even more important, a reduced response to treatment has been shown repeatedly in aged, compared to young animals. The observed reduced treatment efficacy in older animals could be attributed to a combination of age-related mechanisms such as reduced dopaminergic innervation, altered neurotrophic factors, reduced immune response and altered gut microbiome composition. Hence the aged brain represents a more challenging environment for the development of disease-modifying treatments. The lack of incorporating age-dependent cellular and molecular mechanisms in preclinical PD research may have contributed to the limited bench-to-bedside translation of preclinical findings, and why successful disease-modifying treatments remain to be discovered.

In summary, further research should use aged animals and longitudinal whole-body disease modeling for disease investigation and treatment validation. Although the use of aged animals is challenging and resource consuming, a model that better represents clinical disease within the elderly would be more beneficial in the long run, as it will increase translational value and minimize the risk of therapies failing during clinical studies. Furthermore, the use of peripheral and brain imaging biomarkers, as well as the detection of subtype-specific pathology in tissue biopsies, will hopefully progress the field towards earlier diagnosis and finding a subtype-specific cure. This would be especially beneficial for body-first PD patients where damage in the brain is minimal at the earliest time of diagnosis.

Nathalie Van Den Berge is an Assistant professor, group leader Department of Clinical Medicine, Aarhus University, Aarhus, Denmark Department of Nuclear Medicine, Aarhus University Hospital, Aarhus, Denmark. She will be speaking at WPC 2023 on this topic. View the Scientific Program here.

Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions or positions of the World Parkinson Coalition®