Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy

Obeso, José A.; Stamelou, María; Goetz, Christopher G.; Poewe, Werner; Lang, Anthony E.; Weintraub, Daniel; Burn, David J.; Halliday, Glenda M.; Bézard, Erwan; Przedborski, Serge; Lehericy, Stéphane; Brooks, David J.; Rothwell, J C; Hallett, Mark; DeLong, Mahlon R.; Marras, Connie; Tanner, Caroline M.; Ross, G. Webster; Langston, J. William; Klein, Christine; Bonifati, Vincenzo; Jankovic, Joseph; Lozano, Andrés M.; Deuschl, Günther; Bergman, Hagai; Tolosa, Eduardo; Rodríguez‐Violante, Mayela; Fahn, Stanley; Postuma, Ronald B.; Berg, Daniela; Marek, Kenneth; Standaert, David G.; Surmeier, D. James; Olanow, C. Warren; Kordower, Jeffrey H.; Calabresi, Paolo; Schapira, Anthony H.V.; Stoessl, A. Jon

doi:10.1002/mds.27115

Cited by 645 publications

(543 citation statements)

References 294 publications

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“…Fully penetrant PD genes are generally too rare to create large‐scale cohorts, and common variants are insufficiently powerful to identify a sufficiently high‐risk group. However, LRRK‐2 and GBA mutations are relatively common in PD, with sufficiently high penetrance to warrant collection . These mutation carriers are also an important potential group in which to test neuroprotective interventions (targeted therapy like LRRK‐2 inhibitors, enzyme replacement or substrate‐reduction therapy for GBA , etc.).…”

Section: Key Advances In the Last Decadementioning

confidence: 99%

Prodromal Parkinson's Disease: The Decade Past, the Decade to Come

2019

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The past decade has seen a dramatic expansion of the field of prodromal PD. Ten years ago, there were only six known prodromal markers of disease, none of which had more than two studies documenting diagnostic value. We now have at least 16 markers, with as many as 10 prospective studies for a single marker. This review summarizes the major advances over the last decade and speculates about the advances we will see in the decade to come. The most notable advances over the last decade came through the study of high‐risk cohorts (REM sleep behavior disorder and later genetic and autonomic cohorts), the generation of more representative population‐based cohorts for studying prodromal PD, major advances in neuroimaging of early disease stages, the emerging likelihood that tissue biopsy will be able to diagnose prodromal PD, and the coalescence of prodromal markers into discrete criteria. As the next decade dawns, we await increasing precision of sensitivity and specificity estimates of known markers, the discovery of new biomarkers of prodromal disease, improvements in diagnosis using combined methods/criteria (with increasing recognition of prodromal PD as one stage of the full PD spectrum), and ultimately the development of neuroprotective therapy that can be provided at the earliest stages of disease. © 2019 International Parkinson and Movement Disorder Society

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Section: Key Advances In the Last Decadementioning

confidence: 99%

Prodromal Parkinson's Disease: The Decade Past, the Decade to Come

2019

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“…Although textbook chapters and many papers dealing with Parkinson's disease (PD) continue to describe the disorder simply as a disease of substantia nigra dopamine neurons, it is now widely appreciated to be far more complex. PD likely encompasses many genetic–molecular entities unified under a multisystems disorder affecting both the central and peripheral nervous systems, resulting in a broad spectrum of motor and nonmotor features, of which dopamine deficiency is only one of several common denominators . The disorder is relentlessly progressive and within 15 to 20 years of disease onset the expected mortality is 2 to 3 times that of the general population.…”

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confidence: 99%

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

2018

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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 Ca (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.

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“…The most prominent early feature of Parkinson's disease (PD) is a profound loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), associated with Lewy pathology and leading to striatal dopamine depletion . Nigrostriatal neurodegeneration is caused by the interplay of environmental, lifestyle, and genetic factors . The most important risk factor is aging, and the greatest genetic risk factor is a mutation in the GBA gene, which determines earlier onset and more aggressive progression of the disease .…”

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confidence: 99%

Focused ultrasound in Parkinson's disease: A twofold path toward disease modification

et al. 2019

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A major unmet need in Parkinson's disease (PD) is to slow the inexorable progression of neurodegeneration. Clinical trials that evaluated promising pharmacological strategies have repeatedly failed. Nonetheless, the advent of focused ultrasound provides new opportunities toward the goal of developing a safe and effective disease‐modifying therapy for PD. Here we discuss the rationale, possible avenues, and challenges along this path, exploiting the potential of focused ultrasound for (1) performing focal thermal lesions to restore the basic basal ganglia abnormalities associated with dopamine depletion, and (2) transiently opening the blood–brain barrier for targeted delivery of therapeutic agents. First, the classic idea of excitotoxicity mediated by hyperactivity of the subthalamic nucleus suggests that focused ultrasound subthalamotomy may offer a clinically viable disease‐modifying therapy in very‐early PD. Second, the concept of retrograde nigrostriatal neurodegeneration, supported by our recent cortical pathogenic theory of PD, points toward the putamen as a principal site for focused ultrasound blood–brain barrier opening and targeted drug delivery. In principle, both therapeutic strategies—subthalamotomy and putaminal blood–brain barrier opening—could eventually be applied in the same patient. Clinical application is still a long road ahead; nevertheless, focused ultrasound may open a twofold path toward disease modification in PD. © 2019 International Parkinson and Movement Disorder Society

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Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy

Cited by 645 publications

References 294 publications

Prodromal Parkinson's Disease: The Decade Past, the Decade to Come

Prodromal Parkinson's Disease: The Decade Past, the Decade to Come

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

Focused ultrasound in Parkinson's disease: A twofold path toward disease modification

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