+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Disease Modification in Parkinson's Disease: Current Approaches, Challenges, and Future Considerations



Disease Modification in Parkinson's Disease: Current Approaches, Challenges, and Future Considerations



Movement Disorders 33(5): 660-677



The greatest unmet therapeutic need in Parkinson's disease is the development of treatment that slows the relentless progression of the neurodegenerative process. The concept of "disease modification" encompasses intervention types ranging from those designed to slow the underlying degeneration to treatments directed at regenerating or replacing lost neurons. To date all attempts to develop effective disease-modifying therapy have failed. Many reasons have been proposed for these failures including our rudimentary understanding of disease pathogenesis and the assumption that each targeted mechanisms of disease apply to most patients with the same clinical diagnosis. Here we review all aspects of this broad field including general concepts and past challenges followed by a discussion of treatment approaches under the following 4 categories: (1) α-synuclein, (2) pathogenic mechanisms distinct from α-synuclein (most also potentially triggered by α-synuclein toxicity), (3) non-SNCA genetic subtypes of "PD," and (4) possible disease-modifying interventions not directly influencing the underlying PD pathobiology. We emphasize treatments that are currently under active clinical development and highlight a wide range of important outstanding questions and concerns that will need to be considered to advance the field of disease modification in PD. Critically, it is unknown whether the dysfunctional molecular pathways/organelles amenable to modification occur in a sequential fashion across most clinically affected individuals or manifest differentially in independent molecular subtypes of PD. It is possible that there is no "order of disruption" applicable to most patients but, rather, "type of disruption" applicable to subtypes dependent on unknown factors, including genetic variability and other causes for heterogeneity in PD. Knowing when (early vs late), which (eg, synaptic transmission, endosomal sorting and maturation, lysosomal degradation, mitochondrial biogenesis), and in whom (PD subtype) specific disrupted cell pathways are truly pathogenic versus compensatory or even protective, will be important in considering the use of single or combined ("cocktails") putative disease-modifying therapies to selectively target these processes. Beyond the current phase 2 or 3 studies underway evaluating treatments directed at oxidative stress (inosine), cytosolic Ca2+ (isradipine), iron (deferiprone), and extracellular α-synuclein (passive immunization), and upcoming trials of interventions affecting c-Abl, glucagon-like peptide-1, and glucocerebrosidase, it might be argued that further trials in populations not enriched for the targeted pathogenic process are doomed to repeat the failures of the past. © 2018 International Parkinson and Movement Disorder Society.

(PDF emailed within 0-6 h: $19.90)

Accession: 058427293

Download citation: RISBibTeXText

PMID: 29644751

DOI: 10.1002/mds.27360


Related references

Parkinson's disease: Current and future challenges. Neurotoxicology (Little Rock) 23(4-5): 443-450, 2002

Rehabilitation for Parkinson's disease: Current outlook and future challenges. Parkinsonism and Related Disorders 22 Suppl 1: S60-S64, 2016

Exosomes in Parkinson's disease: current perspectives and future challenges. Acs Chemical Neuroscience 2019, 2019

Inpatient management of Parkinson disease: current challenges and future directions. Neurohospitalist 2(1): 28-35, 2012

Safety of disease-modifying drugs for multiple sclerosis in pregnancy: current challenges and future considerations for effective pharmacovigilance. Expert Review of Neurotherapeutics 13(3): 251-60; Quiz 261, 2013

Challenges in detecting disease modification in Parkinson's disease clinical trials. Parkinsonism and Related Disorders 32: 1-11, 2016

Clinical and neuropathological differences between Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies - current issues and future directions. Journal of Neurochemistry 2019, 2019

Current disease modifying approaches to treat Parkinson's disease. Cellular and Molecular Life Sciences 73(7): 1365-1379, 2016

Diarrhoeal disease: current concepts and future challenges. Molecular biological approaches to the epidemiology of diarrhoeal diseases in developing countries. Transactions of the Royal Society of Tropical Medicine and Hygiene 87 Suppl 3: 3-5, 1993

The future challenges in Parkinson's disease. Journal of Neurology 251(3): 361-365, 2004

Diarrhoeal disease: current concepts and future challenges. Intestinal cytokines in inflammatory bowel disease and invasive diarrhoea. Transactions of the Royal Society of Tropical Medicine and Hygiene 87 Suppl 3: 23-26, 1993

Survey on general knowledge on Parkinson's disease in patients with Parkinson's disease and current clinical practice for Parkinson's disease among general neurologists from Southwest China. Clinical Neurology and Neurosurgery 118: 16-20, 2014

Current approaches in the treatment of Parkinson disease. Recenti Progressi in Medicina 80(12): 686-691, 1989

Current approaches in the treatment of Parkinson's disease. Annual Review of Medicine 44: 431-440, 1993

Current approaches to the treatment of Parkinson's Disease. Bioorganic and Medicinal Chemistry Letters 27(18): 4247-4255, 2017