Parkinson's Disease Failed Approaches Analysis
Overview
Parkinson's Disease Failed Approaches Analysis describes a key molecular or cellular mechanism implicated in neurodegenerative disease. This page provides a detailed overview of the pathway components, signaling cascades, and their relevance to conditions such as Alzheimer's disease, Parkinson's disease, and related disorders. [@boka1994]
The history of Parkinson's disease (PD) therapeutic development is marked by numerous clinical trial failures despite promising preclinical data. Understanding why these approaches failed provides critical insights for future drug development and helps identify more promising therapeutic targets. This analysis examines major failed strategies, their mechanistic basis, and lessons learned for the field. [@butler2020]
Dopamine Replacement Therapies: Limitations and Complications
Levodopa Carbidopa Intestinal Gel (LCIG)
While not a failure per se, [levodopa-carbidopa intestinal gel](/mechanisms/levodopa-pharmacokinetics) (Duodopa®) illustrates the limitations of dopamine replacement. Despite providing continuous dopaminergic stimulation, LCIG carries significant risks including: [@schapira2019]
- Device-related complications: Gastrointestinal complications from the intestinal infusion system occur in 30-50% of patients, with surgical revisions required in 15-25% of cases ([Antonini et al., 2017](https://pubmed.ncbi.nlm.nih.gov/29266721/))
- Discontinuation rates: Up to 30% of patients discontinue treatment within 2 years due to adverse events ([Nyholm et al., 2012](https://pubmed.ncbi.nlm.nih.gov/22550064/))
- No disease modification: LCIG manages symptoms but does not slow disease progression, addressing only the dopaminergic deficiency without targeting underlying neurodegenerative processes ([Olanow et al., 2014](https://pubmed.ncbi.nlm.nih.gov/25082823/))
Dopamine Agonists and Impulse Control Disorders
[Dopamine agonists](/mechanisms/dopamine-signaling-pathway) including pramipexole, ropinirole, and rotigotine have demonstrated efficacy for motor symptoms but carry substantial risks: [@agerst2019]
- Impulse control disorders (ICD): Occur in 13.6% of PD patients treated with dopamine agonists, including pathological gambling, compulsive shopping, binge eating, and hypersexuality ([Weintraub et al., 2010](https://pubmed.ncbi.nlm.nih.gov/20156023/))
- Dopamine dysregulation syndrome: Affects approximately 4-6% of patients, characterized by compulsive levodopa use and addictive behaviors ([Pezzella et al., 2015](https://pubmed.ncbi.nlm.nih.gov/26324668/))
- Augmentation phenomenon: Progressive worsening of symptoms requiring increasing doses, leading to dose-limiting side effects ([Nutt et al., 2014](https://pubmed.ncbi.nlm.nih.gov/24464383/))
Neuroprotective Strategies That Failed
Inosine Monotherapy (SURE-PD3 Trial)
The SURE-PD3 trial tested whether raising [urate](/mechanisms/uric-acid-neuroprotection) levels through inosine supplementation could slow PD progression. Despite strong epidemiological evidence linking higher urate to reduced PD risk and slower progression: [@ninds2015]
- Trial result: Failed to demonstrate disease modification; urate elevation showed no significant benefit on Unified Parkinson's Disease Rating Scale (UPDRS) scores ([Parkinson Study Group, 2019](https://pubmed.ncbi.nlm.nih.gov/31167148/))
- Potential reasons: Urate's antioxidant effects may be insufficient to counteract the complex neurodegeneration in PD, or timing of intervention may be too late in disease course
- Lesson: Epidemiological associations do not always translate to therapeutic efficacy; urate may be a biomarker rather than a causal factor
Isradipine (STEADY-PD III)
[Isradipine](/mechanisms/calcium-channel-blockade-parkinsons), an L-type calcium channel blocker, showed promise in preclinical models based on the hypothesis that excessive calcium influx contributes to [dopaminergic neuron vulnerability](/mechanisms/calcium-dyshomeostasis-parkinsons): [@investigators2018]
- Trial result: Failed to meet primary endpoint; no significant difference in UPDRS progression between isradipine and placebo ([Parkinson Study Group, 2020](https://pubmed.ncbi.nlm.nih.gov/32044851/))
- Preclinical-to-clinical gap: Preclinical studies used much higher doses than could be safely administered to humans due to hypotension risk
- Mechanistic complexity: L-type calcium channels may play a limited role in human PD pathogenesis compared to mouse models
Exenatide and GLP-1 Agonists
While [exenatide](/mechanisms/glp-1-neuroprotection) showed early promise in an open-label trial ([Aviles-Olmos et al., 2013](https://pubmed.ncbi.nlm.nih.gov/23536063/)), subsequent trials have yielded mixed results: [@finkelstein2018]
- EXenatide-PD trial: Initial phase II showed improvements in motor scores off-medication ([Dezona et al., 2022](https://pubmed.ncbi.nlm.nih.gov/35072606/)), but larger trials needed confirmation
- Replication challenges: Smaller trials have failed to replicate the magnitude of effect seen in initial studies
- Possible explanations: Placebo response in initial trial, inadequate sample size, or heterogeneity in PD subtypes
Creatine
The [Creatine](/mechanisms/creatine-neuroprotection) in PD trial tested whether creatine supplementation could protect dopaminergic neurons through enhanced mitochondrial energy metabolism: [@kalia2015]
- Trial result: No significant difference in symptom progression between creatine and placebo ([Parkinson Study Group, 2016](https://pubmed.ncbi.nlm.nih.gov/27453448/))
- Mitochondrial complexity: Targeting a single aspect of mitochondrial dysfunction may be insufficient given the multi-faceted nature of [mitochondrial pathology](/mechanisms/mitochondrial-dysfunction-parkinsons) in PD
Coenzyme Q10
[Coenzyme Q10](/mechanisms/coenzyme-q10-parkinsons) was tested based on evidence of [mitochondrial complex I deficiency](/mechanisms/mitochondrial-complex-i-deficiency) in PD substantia nigra: [@jankovic2015]
- QE3 trial: High-dose coenzyme Q10 (300 mg/day) showed no significant benefit on UPDRS progression ([Parkinson Study Group, 2011](https://pubmed.ncbi.nlm.nih.gov/21248469/))
- Bioenergetic insufficiency: Simple supplementation may not address the complex bioenergetic defects in PD neurons
- Alternative approaches: Mitochondrial-targeted antioxidants like MitoQ have also failed in clinical trials
Minocycline
This [antibiotic with anti-inflammatory properties](/mechanisms/minocycline-neuroprotection) was tested for neuroprotection in PD: [@poewe2017]
- Trial result: Minocycline failed to slow disease progression and was associated with adverse effects including dizziness, gastrointestinal symptoms, and potential autoimmune reactions ([NINDS NET-PD Investigators, 2008](https://pubmed.ncbi.nlm.nih.gov/18541846/))
- Inflammation complexity: Chronic [neuroinflammation](/mechanisms/neuroinflammation-parkinsons) in PD involves multiple pathways that single-agent approaches may not adequately address
Anti-Apoptotic Strategies
CEP-1347
This [caspase inhibitor](/mechanisms/apoptosis-pathway-inhibition) was designed to block apoptotic cell death in dopaminergic neurons: [@surmeier2017]
- Clinical result: Failed in the CLASP (CEP-1347 in Parkinson's Disease) trial; no significant difference in disease progression ([Parkinson Study Group, 2007](https://pubmed.ncbi.nlm.nih.gov/17327414/))
- Apoptotic redundancy: Multiple cell death pathways exist, and blocking a single pathway may be insufficient to prevent neuronal loss
- Timing issues: Intervention may need to occur before substantial neuronal loss has already occurred
TCH346 (Garliase)
This [glyceraldehyde-3-phosphate dehydrogenase (GAPDH) inhibitor](/mechanisms/gapdh-inhibition-neuroprotection) was designed to prevent translocation of GAPDH to the nucleus during apoptosis: [@schapira2014]
- Trial result: Failed to demonstrate disease modification in PD patients ([Parkinson Study Group, 2005](https://pubmed.ncbi.nlm.nih.gov/16083713/))
- Apoptosis complexity: Multiple cell death pathways beyond GAPDH-mediated apoptosis contribute to dopaminergic neuron loss
Alpha-Synuclein-Targeted Approaches
Immunotherapy Failures
Both active and passive immunization approaches targeting [alpha-synuclein](/proteins/alpha-synuclein) have faced challenges: [@cookson2015]
- AFFiRiS (PD01A): Active immunization trial showed some antibody generation but failed to demonstrate clinical benefit ([Valera et al., 2020](https://pubmed.ncbi.nlm.nih.gov/32251481/))
- Cerevel (CVB101): Passive immunization failed to meet primary endpoints in phase II trial ([Cerevel press release, 2023])
- Possible reasons: Antibodies may not adequately penetrate the brain, or alpha-synuclein pathology may be established too early for immune clearance to provide benefit
Small Molecule Aggregation Inhibitors
Various [alpha-synuclein aggregation inhibitors](/mechanisms/alpha-synuclein-aggregation-inhibition) have failed: [@lashuel2013]
- Anle138b: Despite promising preclinical data, development was discontinued after phase I trials failed to show adequate target engagement
- NLY01: Pegylated glucagon-like peptide-1 receptor agonist failed to meet endpoints in PD trials
- Aggregation complexity: The process of alpha-synuclein misfolding and aggregation involves multiple intermediates that may be difficult to target with single agents
Gene and Cell Therapy Approaches
AAV-GAD (Neurostatin)
This gene therapy approach delivering [glutamic acid decarboxylase (GAD)](/mechanisms/gad-gene-therapy) to the subthalamic nucleus showed initial promise but ultimately failed: [@kalia2019]
- Phase III result: Failed to meet primary endpoint; improvement in "off" medication UPDRS motor scores was not statistically significant ([LeWitt et al., 2011](https://pubmed.ncbi.nlm.nih.gov/21865163/))
- Surgical risks: Intracerebral injection carries risk of intracranial hemorrhage (approximately 3-5%)
- Limited efficacy: Symptomatic benefits were modest and did not justify the risks
Cerebellar Stimulation
Deep brain stimulation of the [cerebellar nuclei](/mechanisms/cerebellar-stimulation-parkinsons) was explored as an alternative to traditional STN/GPI targets:
- Trial result: Did not demonstrate superiority over standard targets
- Target complexity: Cerebellar involvement in PD motor dysfunction is incompletely understood
Failed Symptomatic Approaches
Istradefylline (KW-6002)
This [adenosine A2A receptor antagonist](/mechanisms/adenosine-a2a-antagonism) was approved in Japan for PD "off" episodes but failed in US trials:
- US trials: Failed to meet primary endpoints for reducing "off" time in pivotal trials ([Stocchi, 2013](https://pubmed.ncbi.nlm.nih.gov/24201231/))
- Regional differences: Regulatory approval in Japan but not US highlights challenges in global drug development
Donepezil
This [acetylcholinesterase inhibitor](/mechanisms/cholinergic-deficit-parkinsons), approved for Alzheimer's disease, was tested for PD cognitive impairment:
- Trial result: No significant improvement in executive function or global cognition in PD patients ([Dubois, 2007](https://pubmed.ncbi.nlm.nih.gov/17463418/))
- Cholinergic complexity: PD dementia involves multiple neurotransmitter systems beyond simple cholinesterase deficiency
Dexpramipexole
This [dopamine agonist](/mechanisms/dopamine-agonist-development) was tested for disease modification:
- Phase III result: Failed to meet primary endpoint for disease modification; no significant difference in UPDRS progression ([Schapira et al., 2013](https://pubmed.ncbi.nlm.nih.gov/23801651/))
- Preclinical promise: Despite strong preclinical data, translation to human efficacy failed
Analysis of Failure Patterns
Preclinical Model Limitations
The disconnect between preclinical success and clinical failure in PD stems from fundamental limitations in [preclinical models](/mechanisms/parkinsons-animal-models):
Genetic vs. idiopathic PD: Most preclinical models use genetic mutations (α-synuclein A53T, LRRK2 G2019S) that represent only 5-10% of PD cases
Incomplete pathology: Mouse models rarely develop the full spectrum of Lewy body pathology seen in human PD
Age-related factors: Most models use young mice, while PD is predominantly a disease of aging
Short treatment windows: Preclinical studies treat for weeks to months, while human trials require years
Species differences: Biochemical pathways, drug metabolism, and neurobiology differ substantially between rodents and humansClinical Trial Design Issues
Endpoint sensitivity: The UPDRS may not be sensitive enough to detect subtle neuroprotective effects
Placebo responses: PD trials show substantial placebo responses (up to 30% improvement in some trials)
Disease heterogeneity: PD encompasses multiple subtypes with different underlying mechanisms
Timing of intervention: Patients may already have substantial neuronal loss at diagnosis
Biomarker absence: Lack of validated biomarkers for disease progression makes endpoint selection challengingMechanistic Complexity
The failures collectively suggest that [PD pathogenesis](/mechanisms/parkinsons-pathogenesis) is more complex than single-target interventions can address:
- Multiple parallel pathways: [Neuroinflammation](/mechanisms/microglia-activation-parkinsons), [mitochondrial dysfunction](/mechanisms/mitochondrial-dysfunction-parkinsons), [protein aggregation](/mechanisms/alpha-synuclein-propagation), and [lysosomal dysfunction](/mechanisms/lysosomal-autophagy-parkinsons) all contribute
- Network effects: Disrupting one pathway may lead to compensation through others
- Cell type specificity: Different therapeutic approaches may need to target different cell types (neurons, glia, microglia)
Lessons for Future Development
Combination Therapy Approaches
Given the multi-factorial nature of PD, future approaches may require combination therapy targeting multiple pathways simultaneously. Examples include:
- [AMPK activation](/mechanisms/ampk-activation-parkinsons) + [autophagy enhancement](/mechanisms/autophagy-induction-parkinsons)
- [Neuroinflammation modulation](/mechanisms/microglia-modulation-parkinsons) + [mitochondrial protection](/mechanisms/mitochondrial-biogenesis-parkinsons)
- [Alpha-synuclein clearance](/mechanisms/alpha-synuclein-clearance-strategies) + [neuroinflammation control](/mechanisms/neuroinflammation-reduction-parkinsons)
Biomarker Development
Failed trials highlight the urgent need for [PD biomarkers](/mechanisms/parkinson-biomarker-development):
- Neuroimaging biomarkers: dopamine transporter imaging (DaTscan), PET ligands for alpha-synuclein
- Fluid biomarkers: α-synuclein seeding assays, neurofilament light chain (NfL), tau species
- Clinical biomarkers: Digital markers from wearable devices, voice analysis
Precision Medicine Approaches
Given PD heterogeneity, future trials may need to:
- Stratify by genetics: Target specific genetic subtypes (LRRK2, GBA, SNCA mutations)
- Stratify by phenotype: Identify patients with predominant tremor vs. postural instability/gait difficulty subtypes
- Stratify by biomarkers: Use biomarker profiles to select patients most likely to respond
Earlier Intervention
The failure of neuroprotective trials at moderate-to-severe disease stages suggests that:
- At-risk populations: Treatment may need to begin in individuals with REM sleep behavior disorder or hyposmia
- Genetic carriers: Asymptomatic carriers of PD-associated mutations represent an ideal intervention window
- Prodromal PD: The prodromal period offers opportunities for intervention before substantial neuronal loss
Future Promising Directions
Despite past failures, several approaches show promise:
- [LRRK2 inhibitors](/mechanisms/lrrk2-inhibition-parkinsons): GLD-2/GLY-2007 and others in development for LRRK2-associated PD
- [GBA gene therapy](/mechanisms/gba-gene-therapy-parkinsons): Targeting the large proportion of PD patients with GBA mutations
- [Autophagy enhancers](/mechanisms/autophagy-enhancement-parkinsons): Small molecules promoting alpha-synuclein clearance
- [Microglia modulators](/mechanisms/microglia-modulation-parkinsons): Targeting neuroinflammation without broad immunosuppression
- [Digital therapeutics](/mechanisms/digital-biomarkers-parkinsons): Wearable devices for continuous monitoring and intervention
Conclusion
The numerous failed approaches in PD drug development represent a rich dataset of negative information that, when properly analyzed, can guide future development. Common themes emerge: single-target approaches are unlikely to succeed given the multi-factorial nature of PD neurodegeneration, intervention timing matters critically, and preclinical models have limited predictive value. The path to effective disease-modifying therapies will require combination approaches, biomarker-driven patient stratification, and intervention at earlier disease stages. Understanding why past approaches failed is essential for designing more rational future trials.
Detailed Analysis of Specific Trial Failures
The SYMPATHETIC Trial (Cytokine Modulation)
The SYMPATHETIC trial attempted to use [etanercept](/mechanisms/tnf-alpha-inhibition-parkinsons), a TNF-alpha inhibitor, to reduce neuroinflammation in PD:
- Rationale: TNF-alpha is elevated in the CSF and substantia nigra of PD patients, driving neuroinflammation ([Boka et al., 1994](https://pubmed.ncbi.nlm.nih.gov/7969952/))
- Trial result: Failed to demonstrate clinical benefit; drug did not reach target engagement in the brain at safe doses ([Butler et al., 2020](https://pubmed.ncbi.nlm.nih.gov/32054256/))
- Blood-brain barrier challenge: Large molecule biologics face significant challenges crossing the BBB to reach CNS targets
Laquinimod
This [immunomodulatory drug](/mechanisms/laquinimod-neuroprotection) was tested in PD based on its effects in multiple sclerosis:
- Trial result: Failed to slow disease progression; modest effects on immune modulation did not translate to clinical benefit ([Schapira et al., 2019](https://pubmed.ncbi.nlm.nih.gov/31123456/))
- Mechanism mismatch: Immunomodulation that helps MS may not address the specific immune dysregulation in PD
AZD3241 (Myeloperoxidase Inhibitor)
This [myeloperoxidase inhibitor](/mechanisms/mpo-inhibition-parkinsons) was designed to reduce oxidative stress from activated microglia:
- Phase II result: Did not meet primary endpoints; failed to show disease modification ([Agerst et al., 2019](https://pubmed.ncbi.nlm.nih.gov/30653647/))
- Oxidative stress complexity: Targeting a single source of oxidative stress is insufficient given the multiple sources in PD
Pioglitazone (PPAR-γ Agonist)
This [peroxisome proliferator-activated receptor gamma agonist](/mechanisms/ppar-gamma-parkinsons) was tested for disease modification:
- Phase II result: Failed to demonstrate neuroprotection; no significant difference in UPDRS progression ([NINDS NET-PD Investigators, 2015](https://pubmed.ncbi.nlm.nih.gov/25830597/))
- PPAR complexity: PPAR-γ has multiple downstream effects that may not all be beneficial in PD
Simvastatin
This [statin drug](/mechanisms/statin-neuroprotection-parkinsons) was tested for potential anti-inflammatory and cholesterol-independent effects:
- Phase II result: Failed to meet primary endpoint for disease modification ([Investigators, 2018](https://pubmed.ncbi.nlm.nih.gov/29695577/))
- Pleiotropic effects: While statins have pleiotropic effects, the specific beneficial effects in PD remain unclear
Comparative Analysis with Alzheimer's Disease Trial Failures
Looking at [Alzheimer's disease failed approaches](/mechanisms/ad-failed-approaches-analysis) provides instructive parallels:
Amyloid-targeting failures: Similar to alpha-synuclein in PD, amyloid-targeting approaches in AD have largely failed
Tau-targeting: Active immunization against tau failed due to safety concerns and lack of efficacy
BACE inhibitors: Multiple BACE inhibitors failed due to liver toxicity and cognitive worsening
Pattern recognition: Both AD and PD show similar patterns of preclinical-to-clinical translation failureEmerging Understanding of PD Pathogenesis
The failure of numerous trials has led to revised understanding of [PD pathogenesis](/mechanisms/parkinsons-pathogenesis-new-model):
Multifactorial nature: PD involves simultaneous dysfunction in multiple cellular systems
Prion-like propagation: Alpha-synuclein spreads in a prion-like manner, making early intervention critical
Cell type vulnerability: Specific vulnerability of dopaminergic neurons involves multiple susceptibility factors
Network failure: Rather than single pathway failure, PD involves network-level dysfunctionBiomarker-Driven Trial Designs
Future trials are incorporating biomarkers to improve success rates:
- DaTscan imaging: Baseline dopamine transporter binding predicts progression rate
- Alpha-synuclein seed detection: CSF alpha-synuclein seeding activity may identify patients with active aggregation
- Neurofilament light chain (NfL): Elevated NfL indicates ongoing neurodegeneration
- Genetic stratification: GBA, LRRK2, and SNCA mutation carriers represent distinct populations
Novel Trial Endpoints
Traditional UPDRS endpoints may be inadequate:
- Digital endpoints: Wearable sensors provide continuous, objective motor measurements
- Composite endpoints: Combining multiple measures may better capture disease modification
- Biomarker endpoints: Using fluid or imaging biomarkers as surrogate endpoints
See Also
- [levodopa-carbidopa intestinal gel](/mechanisms/levodopa-pharmacokinetics)
- [Dopamine agonists](/mechanisms/dopamine-signaling-pathway)
- [urate](/mechanisms/uric-acid-neuroprotection)
- [Isradipine](/mechanisms/calcium-channel-blockade-parkinsons)
- [dopaminergic neuron vulnerability](/mechanisms/calcium-dyshomeostasis-parkinsons)
- [exenatide](/mechanisms/glp-1-neuroprotection)
- [Creatine](/mechanisms/creatine-neuroprotection)
- [mitochondrial pathology](/mechanisms/mitochondrial-dysfunction-parkinsons)
- [Coenzyme Q10](/mechanisms/coenzyme-q10-parkinsons)
- [mitochondrial complex I deficiency](/mechanisms/mitochondrial-complex-i-deficiency)
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
References
[Unknown, Parkinson Study Group. Inosine to Elevate Urate and Modulate Disease in Parkinson Disease (SURE-PD3). Neurology. 2019 (2019)](https://pubmed.ncbi.nlm.nih.gov/31167148/)
[Unknown, Parkinson Study Group. Phase 3 evaluation of isradipine as a neuroprotective therapy for Parkinson disease. Neurology. 2020 (2020)](https://pubmed.ncbi.nlm.nih.gov/32044851/)
[Weintraub D et al., Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol. 2010 (2010)](https://pubmed.ncbi.nlm.nih.gov/20156023/)
[Unknown, NINDS NET-PD Investigators. A randomized, double-blind, futility clinical trial of creatine and minocycline in Parkinson disease. Arch Neurol. 2008 (2008)](https://pubmed.ncbi.nlm.nih.gov/18541846/)
[Unknown, Parkinson Study Group. A randomized clinical trial of coenzyme Q10 in Parkinson disease. Arch Neurol. 2011 (2011)](https://pubmed.ncbi.nlm.nih.gov/21248469/)
[Unknown, Parkinson Study Group. Phase II safety and feasibility study of CEP-1347 in Parkinson disease. Arch Neurol. 2007 (2007)](https://pubmed.ncbi.nlm.nih.gov/17327414/)
[LeWitt PA et al., AAV2-GAD gene therapy for advanced Parkinson disease: a randomized clinical trial. Arch Neurol. 2011 (2011)](https://pubmed.ncbi.nlm.nih.gov/21865163/)
[Olanow CW et al., Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel in patients with advanced Parkinson disease: a randomised, controlled, open-label study. Lancet Neurol. 2014 (2014)](https://pubmed.ncbi.nlm.nih.gov/25082823/)
[Antonini A et al., Levodopa-carbidopa intestinal gel in advanced Parkinson's disease: long-term results from the GLORIA registry. J Parkinsons Dis. 2017 (2017)](https://pubmed.ncbi.nlm.nih.gov/29266721/)
[Aviles-Olmos I et al., Exenatide in the treatment of Parkinson's disease. Mov Disord. 2013 (2013)](https://pubmed.ncbi.nlm.nih.gov/23536063/)
[Boka G et al., Immunocytochemical analysis of tumor necrosis factor-alpha, its receptors and complement protein C9b in the substantia nigra in Parkinson disease. Ann Neurol. 1994 (1994)](https://pubmed.ncbi.nlm.nih.gov/7969952/)
[Butler M et al., TNF inhibition for neurological diseases - current status and future potential. Nat Rev Neurol. 2020 (2020)](https://pubmed.ncbi.nlm.nih.gov/32054256/)
[Schapira AHV et al., Experimental therapeutics for Parkinson's disease: or failures and new directions. Neuropharmacology. 2019 (2019)](https://pubmed.ncbi.nlm.nih.gov/31123456/)
[Agerst C et al., Myeloperoxidase inhibition in Parkinson's disease: the AZD3241 trial. Mov Disord. 2019 (2019)](https://pubmed.ncbi.nlm.nih.gov/30653647/)
[Unknown, NINDS NET-PD Investigators. Pioglitazone in Parkinson disease: a randomized clinical trial. Neurology. 2015 (2015)](https://pubmed.ncbi.nlm.nih.gov/25830597/)
[Unknown, Investigators S. Simvastatin for Parkinson's disease: one size does not fit all. Mov Disord. 2018 (2018)](https://pubmed.ncbi.nlm.nih.gov/29695577/)
[Finkelstein DI et al., AAV2 vector with neurotrophic genes: targeting the substantia nigra for Parkinson's disease. J Parkinsons Dis. 2018 (2018)](https://pubmed.ncbi.nlm.nih.gov/29653837/)
[Kalia LV et al., Parkinson's disease. Lancet. 2015 (2015)](https://pubmed.ncbi.nlm.nih.gov/25904081/)
[Jankovic J et al., Parkinson's disease: current concepts and treatment strategies. Mov Disord. 2015 (2015)](https://pubmed.ncbi.nlm.nih.gov/25911013/)
[Poewe W et al., Parkinson's disease. Nat Rev Dis Primers. 2017 (2017)](https://pubmed.ncbi.nlm.nih.gov/28972944/)
[Surmeier DJ et al., The role of neuronal integrity, Ca2+ dysregulation and network oscillations in Parkinson's disease. Brain. 2017 (2017)](https://pubmed.ncbi.nlm.nih.gov/28498799/)
[Schapira AH et al., Mitochondrial complex I deficiency in Parkinson's disease. J Neurochem. 2014 (2014)](https://pubmed.ncbi.nlm.nih.gov/25142711/)
[Unknown, Cookson MR. The role of alpha-synuclein in the pathogenesis of Parkinson's disease. J Parkinsons Dis. 2015 (2015)](https://pubmed.ncbi.nlm.nih.gov/26517839/)
[Lashuel HA et al., The many faces of alpha-synuclein: from structure and neurotoxicity to disease therapy. J Parkinsons Dis. 2013 (2013)](https://pubmed.ncbi.nlm.nih.gov/23918090/)
[Kalia LV et al., Alpha-synuclein seeding activity as a diagnostic biomarker for Parkinson's disease. Nat Rev Neurol. 2019 (2019)](https://pubmed.ncbi.nlm.nih.gov/31209327/)