Seven Solutions for Neuroprotection in Parkinson's Disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra and accumulation of iron and alpha‐synuclein; it follows a characteristic pattern throughout the nervous system. Despite decades of successful preclinical neuroprotective studies, no drug has then shown efficacy in clinical trials. Considering this dilemma, we have reviewed and organized solutions of varying importance that can be exclusive or additive, and we outline approaches to help generate successful development of neuroprotective drugs for PD: (1) select patients in which the targeted mechanism is involved in the pathological process associated with the monitoring of target engagement, (2) combine treatments that target multiple pathways, (3) establish earliest interventions and develop better prodromal biomarkers, (4) adopt rigorous methodology and specific disease‐relevant designs for disease‐modifying clinical trials, (5) customize drug with better brain biodistribution, (6) prioritize repurposed drugs as a first line approach, and (7) adapt preclinical models to the targeted mechanisms with translational biomarkers to increase their predictive value. © 2020 International Parkinson and Movement Disorder Society

The Disease Modification Conundrum in Parkinson’s Disease: Failures and Hopes

“…However, the use of an enrichment strategy with more restrictive enrollment criteria, narrowing the study population on the basis of well-defined pharmacodynamic biomarkers of the studied therapeutic target, could offer an attractive starting point for success in disease modification in PD. Similar suggestions have been made recently by others ( Espay et al, 2020 ; Devos et al, 2021 ). The enormous investment in disease modification clinical trials over the past couple of decades should convince stakeholders that the strategy of “just keep doing the same” will likely only lead to further waste of time and resources, whereas the concept of a well-informed “less is more” rationale proposed here could not only be scientifically sound, but financially pertinent, as it may yield a new opportunity of turning failure to success.…”

“…The heterogeneity of sporadic PD remains an active field of research to accurately understand pathophysiology and the impact of independent and simultaneous pathologies, with the intention to inform prognosis, and shape therapeutic development for target-/group-, and individual specific disease-modifying therapies ( Mestre et al, 2021 ). Heterogeneity among individual patients is significant to the point that PD may be more appropriately called a syndrome with multiple causes ( Devos et al, 2021 ).…”

“…Preclinical experiments make a painstaking effort to eliminate any and all such heterogeneity, whereas human clinical trials employing phenomenology-based clinical diagnostic criteria to select their study population make no actual effort to homogenize their sample in a way relevant to the tested intervention. While the latter point has been discussed elsewhere ( Devos et al, 2021 ; Espay, 2021 ; Mestre et al, 2021 ), the purpose of animal modeling is to achieve a more accurate representation of a human disease that better supports testing in humans in a continuum where prior studies inform future studies and reduce risk of failures and yield for success. To improve PD preclinical models, better representation of the human sample’s heterogeneity (in age, comorbidities, past environmental exposures, etc.)…”

A Potential Innovative Therapy for Parkinson’s Disease: Selective Destruction of the Pathological Assemblies of Alpha-Synuclein

“…In a recent review Devos and co-workers have reported that "Despite decades of successful preclinical neuroprotective studies, no drug has then shown efficacy in clinical trials." [99]. According to this and other publications, effective neuroprotective therapy is still an unmet need both in PD and MSA.…”

Assessing REM Sleep Behaviour Disorder: From Machine Learning Classification to the Definition of a Continuous Dissociation Index

“…Even though a causal therapy for these diseases does not currently exist, emerging evidence points out that life style modification can dramatically slow down the disease progression [ 3 , 4 ]. Moreover, new neuro-protective drugs are under study [ 5 ], which will be likely effective only if administered in very early, pre-clinical stages of the pathology [ 6 ]. This points out the need for early markers of neurodegeneration.…”