Journal of Parkinson's Disease - Volume 14, issue s2

Authors: Seibler, Philip | Streubel-Gallasch, Linn | Klein, Christine

Article Type: Review Article

Abstract:  Family studies have linked several rare genetic variants to hereditary forms of Parkinson’s disease (PD). In addition to these monogenic forms, many PD cases are associated with genetic risk factors. Asymptomatic individuals carrying pathogenic variants linked to PD are at risk of developing the disease later in life, thereby providing a unique opportunity for the detection of the earliest pathophysiological and later clinical changes and, importantly, also of protective and compensatory features and mechanisms. However, the rarity of monogenic PD-causing variants is a major challenge of this approach. In this review, we discuss recent advances in the search for biomarkers …in the prodromal/earliest phase of genetically linked PD. Show more

Keywords: Biomarker, genetic Parkinson’s disease, prodromal Parkinson’s disease, seeding amplification assay, neuroimaging marker

DOI: 10.3233/JPD-240155

Citation: Journal of Parkinson's Disease, vol. 14, no. s2, pp. S345-S351, 2024

Authors: Theis, Hendrik | Pavese, Nicola | Rektorová, Irena | van Eimeren, Thilo

Article Type: Review Article

Abstract: Assessing imaging biomarker in the prodromal and early phases of Parkinson’s disease (PD) is of great importance to ensure an early and safe diagnosis. In the last decades, imaging modalities advanced and are now able to assess many different aspects of neurodegeneration in PD. MRI sequences can measure iron content or neuromelanin. Apart from SPECT imaging with Ioflupane, more specific PET tracers to assess degeneration of the dopaminergic system are available. Furthermore, metabolic PET patterns can be used to anticipate a phenoconversion from prodromal PD to manifest PD. In this regard, it is worth mentioning that PET imaging of inflammation …will gain significance. Molecular imaging of neurotransmitters like serotonin, noradrenaline and acetylcholine shed more light on non-motor symptoms. Outside of the brain, molecular imaging of the heart and gut is used to measure PD-related degeneration of the autonomous nervous system. Moreover, optical coherence tomography can noninvasively detect degeneration of retinal fibers as a potential biomarker in PD. In this review, we describe these state-of-the-art imaging modalities in early and prodromal PD and point out in how far these techniques can and will be used in the future to pave the way towards a biomarker-based staging of PD. Show more

Keywords: MRI, PET, neuroimaging, Parkinson’s disease, progression, diagnosis, prodromal, biomarker

DOI: 10.3233/JPD-230385

Citation: Journal of Parkinson's Disease, vol. 14, no. s2, pp. S353-S365, 2024

Article Type: Other

Citation: Journal of Parkinson's Disease, vol. 14, no. s2, pp. S367-S367, 2024

Authors: Yamakado, Hodaka | Takahashi, Ryosuke

Article Type: Review Article

Abstract: There is an estimated 35–45% loss of striatal dopamine at the time of diagnosis of Parkinson’s disease (PD), and cases clinically diagnosed in the early stages may already be pathologically in advanced stages. Recent large-scale clinical trials of disease-modifying therapies (DMT) also suggest the necessity of targeting patients at earlier stages of the disease. From this perspective, the prodromal phase of PD is currently the focus of attention, emphasizing the need for a prodromal mouse model that accurately reflects the pathophysiology, along with early biomarkers. To establish prodromal animal model of PD with high face validity that reflects the disease …state, the model must possess high construct validity that accurately incorporates clinical and pathological features in the prodromal phase. Furthermore, as a preclinical model of DMT, the model must possess high predictive validity to accurately evaluate the response to intervention. This review provides an overview of animal models which reflect the characteristics of prodromal PD, including alpha-synuclein (aS) accumulation and associated early non-motor symptoms, with a focus on the aS propagation model and genetic model. In addition, we discuss the challenges associated with these models. The genetic model often fails to induce motor symptoms, while aS propagation models skip the crucial step of initial aS aggregate formation, thereby not fully replicating the entire natural course of the disease. Identifying factors that induce the transition from prodromal to symptomatic phase is important as a preclinical model for DMT to prevent or delay the onset of the disease. Show more

Keywords: Parkinson’s disease, prodromal Parkinson’s disease, non-motor, prodromal, animal model, synuclein, propagation, preclinical model, disease-modifying therapy, transgenic

DOI: 10.3233/JPD-230393

Citation: Journal of Parkinson's Disease, vol. 14, no. s2, pp. S369-S379, 2024

Authors: Crotty, Grace F. | Ayer, Samuel J. | Schwarzschild, Michael A.

Article Type: Review Article

Abstract: For decades the greatest goal of Parkinson’s disease (PD) research has often been distilled to the discovery of treatments that prevent the disease or its progression. However, until recently only the latter has been realistically pursued through randomized clinical trials of candidate disease-modifying therapy (DMT) conducted on individuals after they received traditional clinical diagnosis of PD (i.e., tertiary prevention trials). Now, in light of major advances in our understanding of the prodromal stages of PD, as well as its genetics and biomarkers, the first secondary prevention trials for PD are beginning. In this review, we take stock of DMT trials …to date, summarize the breakthroughs that allow the identification of cohorts at high risk of developing a traditional diagnosis of PD, and describe key design elements of secondary prevention trials and how they depend on the prodromal stage being targeted. These elements address whom to enroll, what interventions to test, and how to measure secondary prevention (i.e., slowed progression during the prodromal stages of PD). Although these design strategies, along with the biological definition, subtype classification, and staging of the disease are evolving, all are driven by continued progress in the underlying science and integrated by a broad motivated community of stakeholders. While considerable methodological challenges remain, opportunities to move clinical trials of DMT to earlier points in the disease process than ever before have begun to unfold, and the prospects for PD prevention are nowtangible. Show more

Keywords: Prevention, secondary prevention, Parkinson’s disease, prodrome, disease modifying therapy, randomized clinical trial, REM sleep behavior disorder, synuclein, LRRK2, GBA

DOI: 10.3233/JPD-240164

Citation: Journal of Parkinson's Disease, vol. 14, no. s2, pp. S381-S393, 2024

Authors: Oosterhof, Thomas H. | Darweesh, Sirwan K.L. | Bloem, Bastiaan R. | de Vries, Nienke M.

Article Type: Research Article

Abstract: The increasing prevalence of people with Parkinson’s disease (PD) necessitates a high priority for finding interventions to delay or even prevent the onset of PD. There is converging evidence that exercise may exert disease-modifying effects in people with clinically manifest PD, but whether exercise also has a preventive effect or is able to modify the progression of the pathology in the prodromal phase of PD is unclear. Here we provide some considerations on the design of trials that aim to prevent PD through exercise. First, we discuss the who could benefit from exercise, and potential exercise-related risks. Second, we …discuss what specific components of exercise mediate the putative disease-modifying effects. Third, we address how methodological challenges such as blinding, adherence and remote monitoring could be handled and how we can measure the efficacy of exercise as modifier of the course of prodromal PD. We hope that these considerations help in designing exercise prevention trials for persons at risk of developing PD. Show more

Keywords: Exercise, prevention, Parkinson’s disease, disease modification, considerations, non-pharmacological,treatment

DOI: 10.3233/JPD-240091

Citation: Journal of Parkinson's Disease, vol. 14, no. s2, pp. S395-S406, 2024

Authors: Mahlknecht, Philipp | Poewe, Werner

Article Type: Review Article

Abstract: Slowing or halting progression continues to be a major unmet medical need in Parkinson’s disease (PD). Numerous trials over the past decades have tested a broad range of interventions without ultimate success. There are many potential reasons for this failure and much debate has focused on the need to test ‘disease-modifying’ candidate drugs in the earliest stages of disease. While generally accepted as a rational approach, it is also associated with significant challenges around the selection of trial populations as well as trial outcomes and durations. From a health care perspective, intervening even earlier and before at-risk subjects have gone …on to develop overt clinical disease is at the heart of preventive medicine. Recent attempts to develop a framework for a biological definition of PD are aiming to enable ‘preclinical’ and subtype-specific diagnostic approaches. The present review addresses past efforts towards disease-modification, including drug targets and reasons for failure, as well as novel targets that are currently being explored in disease-modification trials in early established PD. The new biological definitions of PD may offer new opportunities to intervene even earlier. We critically discuss the potential and challenges around planning ‘disease-prevention’ trials in subjects with biologically defined ‘preclinical’ or prodromal PD. Show more

Keywords: Parkinson’s disease (PD), prodromal PD, preclinical PD, neuroprotection, disease-prevention, disease-modification, biological definition of PD

DOI: 10.3233/JPD-230354

Citation: Journal of Parkinson's Disease, vol. 14, no. s2, pp. S407-S421, 2024