Open research questions in Parkinson's Disease Mechanisms and Treatments
2,117 gap statements mined from Parkinson's Disease Mechanisms and Treatments papers in our 7.9M-paper local library, which holds 7,415 papers on the topic — drawn mostly from each paper's own stated research gap, future-work, challenge and limitation notes, and its abstract. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one.
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What the literature leaves open
The relationship between DDC, prolactin, and AOC3 levels and dopaminergic treatment is not well understood.
Dopamine replacement therapy modulates DDC, prolactin and AOC3 levels in Parkinson’s disease · 2026 · DOIThe main strength of this study is its focus on a clinically relevant and underexplored question in a Peruvian Parkinson’s disease population: whether motor stage is associated with non-motor symptom severity.
Hoehn and Yahr Stage and Non-Motor Symptom Burden in Parkinson’s Disease: A Cross-Sectional Study in Peru · 2026 · DOITheir clinical characteristics—including age, levodopa equivalent daily dose, and the distance between their baseline event-matrix profile and the GMM inter-subtype boundary—have not been systematically characterised in the present analysis.
Imaging-Validated Parkinson’s Subtypes via Sensitivity Grid SuStaIn Approximation and Conditional Normalising Flow · 2026 · DOIAn important limitation of this study was the use of different testing platforms according to their availability over time, resulting in nonuniform analysis of genes and variants across the cohort. Pro392Leu variant in one patient, as it has rarely been reported in PD, and it is more frequently reported in frontotemporal dementia and amyotrophic lateral sclerosis.
Additionally, the absence of established covariates in the current PVI framework represents a significant limitation that must be acknowledged.
Selective Neuronal Vulnerability to Alpha-Synuclein Pathology in Parkinson’s Disease: A Critical Review of Mechanistic Rationale and Biomarker Stratification · 2026 · DOIFuture work will focus on larger multi-site datasets, integration of additional biomarkers such as gait and speech features, and extension to Transformer-based architectures.
A Multimodal Deep Learning Framework for Parkinson's Disease Classification Using GLCM Features from MRI and SPECT Imaging · 2026 · DOIDempster's rule is well suited to weakly conflicting evidence and the conflict distribution on PPMI concentrates near zero, but PCR6 motivates future work.
A Multimodal Evidential Deep Learning Framework with Dempster–Shafer Fusion for Parkinson's Disease Detection from MRI and Clinical Data · 2026 · DOIThese recommendations aid clinicians in making important decisions in settings where neuropsychology resources are limited.
Best practice guidelines for the diagnosis, evaluation, and management of cognitive disorders in Parkinson’s disease · 2026 · DOIAlthough the guideline development process did not reveal sufficient evidence to support clinical recommendations in these fields, future iterations should focus closely on these rapidly evolving areas. Biomarkers aim to enhance early diagnosis, prognosis, and treatment of cognitive disorders in PD.
Best practice guidelines for the diagnosis, evaluation, and management of cognitive disorders in Parkinson’s disease · 2026 · DOIFuture work will focus on resolving the above limitations and optimizing PF structural modification to enhance CNS bioavailability, thereby promoting the translational application of PF as a promising natural neuroprotective agent for counteracting toxin-triggered neuronal injury. Nevertheless, several important limitations of the present study should be explicitly addressed.
Neuroprotective Mechanisms of Paeoniflorin in Parkinson’s Models: Involvement of BDNF-Dependent PI3K/Akt and ERK/CREB Pathways · 2026 · DOIFuture multicenter longitudinal studies incorporating comprehensive small-fiber evaluation and histological validation are warranted to confirm the clinical utility of SWE in this population and to elucidate the temporal dynamics of nerve stiffness changes across the disease course.
Application of Shear Wave Elastography in Assessing Peripheral Neuropathy in Parkinson’s Disease · 2026 · DOIHowever, despite growing interest, the prognostic value of peripheral inflammatory biomarkers for long-term PD progression, as well as their differential associations across patient subgroups defined by clinical severity, have not been fully elucidated.
Peripheral inflammation predicts motor, cognitive, and disease progression in Parkinson’s disease: A 4-year longitudinal study from the PPMI cohorts · 2026 · DOIDifferent studies may draw inconsistent conclusions, indicating that an accurate understanding of the epigenetic landscape requires more rigorous and systematic analyses.
Epigenetic mechanisms of Parkinson's disease and potential epigenetic-based therapeutics · 2026 · DOIInitiatives like the Young Pax association in Portugal demonstrate the value of patientled support networks and should be replicated and scaled globally.
Global, regional, and national burden of Early-onset Parkinson’s disease: A comprehensive analysis and forecast, 1990–2021 · 2026 · DOILimitations of the current study include the use of a single comparator (HARS) without a diagnostic interview, and the time-frame mismatch between MDS-UPDRS administered only in the ON state versus the state-anchored HARS ratings that may introduce measurement inconsistencies that could impact estimate accuracies.
Screening performance of the MDS-UPDRS anxiety item in Parkinson’s disease: Comparison to the Hamilton anxiety rating scale · 2026 · DOIFurther work is needed to define endpoints for early PD, thresholds for meaningful change, and optimal duration for clinical trials of disease modifying treatments in early PD. Limitations of this study include a smaller sample size with predominantly white participants.
Three years later: tracking bothersome symptoms and impacts for people with early Parkinson’s disease · 2026 · DOIFuture studies with pathologically verified cohorts, larger multicenter datasets, and longitudinal follow-up are warranted to validate the diagnostic utility of COP-derived features.
Balance biomarker for early differentiation of Parkinson’s disease and multiple system atrophy with parkinsonian type · 2026 · DOIFor the differential diagnosis of atypical parkinsonian syndromes, future studies may consider incorporating other imaging biomarkers, such as MRPI, midbrain morphometric measures, and putaminal abnormalities, and extending clinical follow-up to improve disease-classification performance. The absence of an external validation cohort is an important limitation.
Patterns of iron deposition and classification in parkinsonian syndromes: a quantitative susceptibility mapping study · 2026 · DOIMajor limitations persist, including incomplete longitudinal validation, uncertain prognostic value, and a lack of consensus on how biomarker status should inform individual clinical decisions. Critically, well-validated intermediate endpoints linking biomarker modulation to durable functional outcomes are lacking, a gap that continues to undermine efforts toward disease-modifying therapy.
Our results illustrated the important but probably under-recognized contribution by rare variants towards sporadic, late-onset PD, and supplemented the existing literature which is largely derived from Caucasian populations with information on the genetics of PD in Chinese populations.
Rare Variants May Influence Disease Risk and Clinical Features in Sporadic Late-Onset Chinese Parkinson’s Disease Patients · 2026 · DOIAt present, there are few studies on the application of rTMS in the treatment of fatigue in PD, which can be used as a potential treatment in the future.
Caregiver involvement was characterized only as availability at treatment initiation rather than the amount or nature of support; baseline comorbidities were ascertained from clinical records without standardized severity grading or harmonized diagnostic criteria; and adverse-event severity was not prospectively graded across centers.
Real-world outcomes and early discontinuation of foslevodopa/foscarbidopa in Parkinson’s disease · 2026 · DOIHowever, sex differences appear to exist in access to DATs as well, with differences about the indication and management of the DAT being poorly studied, and particularly, without previously published data in Spain.
Sex Differences in the Treatment of People with Parkinson’s Disease with a Device-Aided Therapy: A Prospective Real-World Study · 2026 · DOIImportantly, the difference was not limited to an unadjusted comparison: the group-by-time interaction remained significant in the principal adjusted RM-ANOVA model and in a sensitivity model that additionally accounted for changes in motor and non-motor symptom burden.
Greater and Clinically Meaningful Improvement in Health-Related Quality of Life After Device-Aided Therapy in Younger Patients Earlier Within Advanced Parkinson’s Disease: Real-World Evidence from the DATs-PD GETM Spanish Registry · 2026 · DOIPain, particularly musculoskeletal pain, appears common in the early stages of PD and may initially be underrecognized conditions, potentially delaying diagnosis.
Pain and sensory abnormalities in prodromal and early Parkinson's disease: mechanisms, assessment, and clinical implications · 2026 · DOI
Most-cited papers in Parkinson's Disease Mechanisms and Treatments
- α-Synuclein in Lewy bodies · Nature · 1997 · 7,200 citations
- Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease · Science · 1997 · 7,161 citations
- Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism · Nature · 1998 · 4,343 citations
- Chronic Parkinsonism in Humans Due to a Product of Meperidine-Analog Synthesis · Science · 1983 · 3,962 citations
- α-Synuclein Locus Triplication Causes Parkinson's Disease · Science · 2003 · 3,859 citations
- Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1 · Science · 2004 · 3,083 citations
- Diagnosis and Treatment of Parkinson Disease · JAMA · 2020 · 2,659 citations
- Pathological α-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice · Science · 2012 · 2,381 citations
- D 1 and D 2 Dopamine Receptor-regulated Gene Expression of Striatonigral and Striatopallidal Neurons · Science · 1990 · 2,354 citations
- Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism · Science · 2003 · 2,351 citations
Most recent work
- Molecular Mechanisms of 6PPD and 6PPD-Q Toxicity in Neurodegenerative Diseases: A Network Toxicology and Experimental Validation Study · Toxics · 2026
- Fixed-Dose Tavapadon for Early Parkinson Disease · JAMA Neurology · 2026
- Mitochondrial DNA drives NLRP3-IL-1β axis activation in microglia by binding to NLRP3, leading to neurodegeneration in Parkinson’s disease models · Cell Death and Disease · 2026
- Tavapadon as Adjunctive Treatment for Parkinson Disease · JAMA Neurology · 2026
- Artificial intelligence and multi-omics nominate TAZ as an insomnia-related diagnostic and druggable target for Parkinson’s disease patients · Frontiers in Aging Neuroscience · 2026
- Clinical and Imaging Characteristics of Parkinson's Disease with Negative Alpha‐Synuclein Seed Amplification Assay · Movement Disorders · 2026
- Early Autonomic Burden in Prodromal Parkinson's Disease Predicts Cognitive Impairment · Movement Disorders · 2026
- CSF α-Synuclein Seed Amplification Assays and Skin Immunofluorescence · Neurology · 2026
- Glucosylceramide-induced ectosomes propagate pathogenic α-synuclein in Parkinson’s disease · Nature Cell Biology · 2026
- Co‐ and Multi‐Pathologies in Parkinson's Disease: An International Parkinson and Movement Disorder Society Scientific Issues Committee Review · Movement Disorders · 2026
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