BackgroundNeuropsychiatric symptoms such as anxiety and depression substantially impair quality of life in Parkinson's disease (PD), yet the underlying neural circuits remain poorly defined. The MitoPark (MP) mouse, a dopaminergic mitochondrial dysfunction model, recapitulates both motor and non-motor features of PD.ObjectiveTo determine whether the sustained-release GLP-1 receptor agonist PT320 (exenatide) alleviates anxiety- and depression-like behaviors in MP mice and to identify the involved neural substrates.MethodsThe temporal progression of anxiety- and depression-like behaviors was characterized in MP mice. PT320 was administered biweekly starting at either 5 weeks (early treatment) or 15 weeks (late treatment), with longitudinal evaluation until 20 weeks. Behavioral outcomes were correlated with molecular, transcriptomic, and neurochemical analyses in the nucleus accumbens (NAc), including Western blotting, bulk RNA sequencing, fast-scan cyclic voltammetry, and tyrosine hydroxylase immunostaining.ResultsEarly PT320 treatment effectively prevented the emergence of anxiety- and depression-like phenotypes in MP mice. Behavioral improvement was associated with restoration of BDNF signaling and activation of the Akt-CREB pathway in the NAc. Transcriptomic analysis revealed increased expression of Akt3, CREB, BDNF, and TrkB, along with modulation of genes related to mitochondrial homeostasis. Late PT320 treatment partially ameliorated neuropsychiatric deficits, coinciding with enhanced phasic dopamine release and recovery of tyrosine hydroxylase expression in the NAc.ConclusionsThese findings identify the NAc as a critical regulator of affective disturbances in this PD model. By restoring neurotrophic signaling and dopaminergic function, PT320 represents a promising therapeutic strategy for PD-related anxiety and depression. A long-acting drug may improve symptoms of anxiety and depression in Parkinson's diseaseParkinson's disease is widely known for movement problems such as tremor and stiffness. However, many people with Parkinson's disease also experience anxiety, depression, apathy, and difficulties with thinking. These non-motor symptoms can appear early, greatly affect quality of life, and are often difficult to manage. Despite their importance, the brain changes that contribute to these emotional symptoms are not yet fully understood. In this study, we used a well-established mouse model of Parkinson's disease that shows both movement problems and emotional changes similar to those seen in patients. We examined whether a long-acting drug called PT320, which has shown protective effects in the brain, could reduce anxiety and depression-like behaviors. The drug was given either early, before emotional symptoms appeared, or later, after symptoms had already developed. We found that early treatment with PT320 prevented the development of anxiety- and depression-like behaviors as the disease progressed. These benefits were associated with healthier activity in a brain region involved in motivation and emotional control. When treatment was started at a later stage, only partial improvement was observed. Overall, our findings suggest that emotional symptoms in Parkinson's disease are closely linked to changes in specific brain circuits and that early treatment may be especially important. This study highlights PT320 as a promising strategy for addressing anxiety and depression in Parkinson's disease and supports the idea that early management of non-motor symptoms could improve long-term outcomes.
Addiction is a chronic relapsing condition characterized by compulsive reward seeking and impaired behavioral control, associated with major individual and societal burden. Mechanistic investigation in humans remains constrained by ethical limitations, uncontrolled exposure histories, and ecological confounds. Parkinson's disease treated with dopamine replacement therapy provides a human framework for investigating addiction-relevant mechanisms under controlled dopaminergic modulation. We performed a narrative synthesis of clinical, neuropsychological, pharmacological, neuroimaging, and electrophysiological evidence linking impulse control disorders and dopamine dysregulation syndrome in Parkinson's disease to dimensional and circuit-based models of addiction. We examined phenotypic and neurobiological convergences, experimental opportunities, and translational relevance while outlining its boundary conditions. A subset of Parkinson's disease patients exposed to dopamine replacement treatment develops impulse control disorders and dopamine dysregulation syndrome. Impulse control disorders comprise heterogeneous behavioral phenotypes that share selected dimensions with behavioral addictions, whereas dopamine dysregulation syndrome most closely approximates pharmacological substance use disorders. These phenotypes share selected addiction-related dimensions, including craving, impaired control, compulsive reward-seeking, and persistence despite harm, while showing partial clinical and neurobiological convergence with behavioral addictions and substance use disorders. Parkinson's disease patients with neuropsychiatric fluctuations may represent a sensitized vulnerability state in which dopaminergic modulation dynamically influences reward processing, motivation, and compulsive behaviors. Parkinson's disease under dopamine replacement therapy enables within-subject dopaminergic manipulation, longitudinal observation, prospective assessment of vulnerability traits, multimodal neurobiological investigation, and reduced environmental confounding. It therefore provides a unique human window for investigating addiction-relevant mechanisms under controlled dopaminergic modulation, complementing animal models while remaining constrained by disease-specific boundary conditions.
BackgroundCognitive behavioral therapy (CBT) has emerged as a promising intervention in Parkinson's disease (PD), although the available evidence remains heterogeneous in design and quality.ObjectiveThe present mixed method systematic review aims to synthesize the evidence on CBT in people with PD (PwPD) and caregivers, focusing on clinical applications and therapeutic outcomes across symptom domains.MethodsA systematic search of PubMed, Web of Science, Scopus and Cochrane databases was conducted for studies published between 1980 and 2025, following PRISMA guidelines. Eligible studies evaluated clinical applications and therapeutic outcomes of CBT-based interventions in PwPD and/or caregivers and included randomized controlled trials, observational studies, case series and single-case reports. Findings were synthesized narratively, and certainty of evidence was assessed using a simplified GRADE approach.ResultsFifty-four studies met inclusion criteria. The most robust evidence was observed for depression, with several RCTs supporting the efficacy of CBT, resulting in moderate certainty of evidence. Evidence for anxiety and sleep disorders suggests potential benefit; however, certainty was low due to heterogeneity and small sample sizes. Evidence for impulse control disorders, cognitive outcomes, motor symptoms, and caregiver -related outcomes remain limited, with low to very low certainty, Effects on motor symptoms were inconsistent and likely indirect.ConclusionsCBT represents a flexible and transdiagnostic intervention for treating non-motor symptoms in PwPD and for caregivers. While moderate-certainty evidence supports CBT use for depression, evidence for other domains remains limited. These findings should be interpreted with caution, and further large-scale, well designed RCTs are needed to strengthen the evidence base and clarify optimal therapeutic targets and delivery format. Cognitive-behavioral therapy for mood and other non-motor symptoms in people with Parkinson and caregivers.Parkinson's disease is usually know for movement issues such as tremor or slowness. However, many people also experience depression, anxiety, sleep distubances, cognitive difficulties, impulse-control disorders. These symptoms can strongly affect daily life and quality of life, and they can also increase stress and burden for caregivers.Cognitive-behavioral therapy or CBT is a psychotherapy that helps people identify unhelpful thoughts and behaviors and replace them with more helpful ones. CBT can include techniques such as behavioral activation (doing more meaningful activities), cognitive restructuring (changing unhelpful thinking patterns), and strategies tailored to specific problems (for example CBT for insomnia).In this systematic review, we searched major scientific databases for studies published between 1980 and 2025 that tested CBT-based interventions in people with Parkinson's disease and/or their caregivers. In total, 54 studies met the inclusion criteria.Overall, the strongest evidence supports CBT for depression in Parkinson's disease, with many studies showing meaningful symptom improvement. Evidence for anxiety has increased especially when anxiety is the main treatment target. CBT for insomnia also shows consistent benefits fot subjective sleep outcomes. There is promising but more limited evidence that CBT may help impulse-control disorders, daily functioning and caregiver burden, particularly when caregivers are involved in treatment. Effects on motor symptoms were inconsistent and seem indirect rather than a direct improvement in movement.In summary, CBT appears to be a flexible and useful option for several non-motor symptoms in PD. Future larger and well-designed studies are needed to clarify which patients benefit most and how to deliver CBT in the most effective and accessible way. These findings support integrating psychological care into routine Parkinson's disease management whenever possible.
This study compares the effects of assistive devices (ADs) on mobility and dual-task performance in individuals with and without Parkinson's disease. We hypothesize that bilateral ADs will increase time and dual-task (DT) performance in both groups, with greater changes in people with Parkinson's disease (PwPD). This quasi-experimental study assessed performance on the Timed-Up-and-Go with AD (TUG) and Timed-Up-and-Go-Cognitive (TUG-COG) across six different assistive devices in two groups: PwPD (n = 11, 73.4 ± 4.92 years); older adults without PD (n = 7, 72.1 ± 8.4 years). A repeated measures ANOVA with Bonferroni correction showed a significant main effect of ADs on TUG and TUG-COG time (both p < 0.001). In PwPD, TUG with AD time differed significantly between devices: single-point cane and large-based quad cane (LBQC) (p = 0.044), pick-up walker (PUW) (p = 0.001), rollator (p = 0.014), and LBQC and PUW (p = 0.007). Friedman's ANOVA revealed significant differences in TUG-COG across devices in PwPD (p < 0.001) and older adults (p = 0.003). No significant differences in the effect of assistive devices were found between PwPD and older adults. Bilateral ADs, such as the pick-up walker, led to larger differences in TUG performance compared to unilateral devices. Most outcomes were similar between groups, suggesting device choice, rather than the diagnosis of Parkinson's disease, may impact performance in the earlier stages of the diagnosis. Point 1: Assistive device prescription should be based on functional task demands, rather than diagnosis. No significant device × group interactions were observed, indicating that although individuals with Parkinson’s disease demonstrated slower baseline mobility, the introduction of assistive devices affected mobility performance similarly to age-matched controls. These findings suggest that, for individuals in the early stages of Parkinson’s disease, assistive device prescription should emphasize functional task demands, device complexity, and individual performance rather than diagnosis alone.Point 2: Assistive device training should occur in dual task conditions as use of an unfamiliar device creates a cognitive-motor challenge impacting mobility. Introducing an assistive device alone resulted in decreased mobility performance, even among individuals who did not routinely require one, suggesting that device management functions as an additional motor task. Clinicians should incorporate structured practice under dual-task conditions, including turning, transfers, and divided-attention activities, to promote safe and efficient use in real-world environments.Point 3: Device complexity should be considered along with other factors during selection. More supportive devices, particularly the pick-up walker, produced the greatest performance cost despite providing increased stability. In contrast, simpler devices such as the single-point cane and small-based quad cane more closely approximated baseline mobility. Rehabilitation professionals should balance stability with maneuverability, cognitive demands, and efficiency when selecting the least restrictive device that safely meets an individual’s functional needs.
Traditional classifications of Parkinson's disease (PD), such as tremor-dominant and postural instability/gait difficulty (PIGD) types, are useful for prognosis but offer limited guidance for individualized interventions. This case series descriptively explores clinically observed movement patterns, referred to as rigid, loose, and hemi types, to illustrate how rehabilitation strategies were adapted for each case. Three individuals with PD were categorized by their predominant motor presentation and completed a three-month intensive rehabilitation program. The rigid type received gait training with visual feedback and rhythmic cueing. The loose type underwent trunk- and hip-focused strengthening combined with aerobic training to improve movement control. The hemi type received laterality-focused sensorimotor training progressing from single-joint to coordinated multi-joint movements. All participants showed improvements in gait symmetry, postural control, and motor function, with reductions in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III and Parkinson's Disease Questionnaire-39 (PDQ-39) scores and enhanced spatiotemporal gait parameters. A movement-based perspective may serve as a practical clinical framework for considering individualized rehabilitation strategies. These findings should be interpreted as exploratory and hypothesis-generating.
Helicobacter pylori (HP) infection has been implicated in modifying treatment response and clinical outcomes in Parkinson's disease(PD). This study aimed to evaluate the effect of HP eradication therapy on motor symptoms, non-motor symptom burden, and quality of life in patients with PD. We conducted a double-blind, randomised, placebo-controlled trial in which HP-positive adults with PD were randomised (1:1) to standard triple eradication therapy (omeprazole 20 mg, amoxicillin 1000 mg, and clarithromycin 500 mg, each twice-daily for 14 days) or matched placebo. The primary outcome was the MDS-Unified Parkinson's Disease Rating Scale(MDS-UPDRS) Part III motor score in the ON medication state at 12 weeks. Secondary outcomes included total MDS-UPDRS score, Non-Motor Symptoms Scale (NMSS) score, and Parkinson's Disease Questionnaire-39 (PDQ-39) summary index score. Out of eighty participants who underwent urea-breath testing, 34 tested positive. Of them, 30 participants were randomised to the two treatment groups. The primary outcome did not differ significantly between groups at 12 weeks (mean difference -3.9; 95% CI -15.5 to 7.6; p=0.49), which was unchanged after adjustment for baseline scores (p=0.13). No significant between-group differences were observed in total MDS-UPDRS score(mean difference -0.13; 95% CI -22.1 to 21.8; p=0.99), NMSS score(mean difference 23.3; 95% CI-8.8 to 55.4; p=0.15), or PDQ-39 scores(mean difference -7.1; 95% CI -35.4 to 21.1; p=0.61). HP eradication therapy did not improve motor symptoms, non-motor symptom burden, or quality of life in PD patients over 12 weeks. These findings do not support routine HP eradication as an adjunctive strategy for improving PD symptom control. CTRI/2019/04/018524.
Drooling is a common non-motor symptom in Parkinson's disease (PD) and can substantially impair quality of life, but its underlying neural mechanisms remain incompletely understood. Quantitative susceptibility mapping (QSM) provides a non-invasive approach for assessing susceptibility alterations related to brain iron deposition. This cross-sectional study aimed to investigate QSM-derived susceptibility alterations in PD patients with drooling (PD-DR) and to explore their associations with drooling severity. A total of 103 participants, including 38 PD-DR, 23 PD patients without drooling (PD-NDR), and 42 healthy controls (HC), underwent three-dimensional (3D) magnetic resonance imaging including regular sequences and QSM. Voxel-wise whole-brain analysis and region of interest (ROI)-based analysis focusing on subcortical nuclei were performed to compare magnetic susceptibility values among groups, with voxel-wise significance set at voxel-level P<0.001 and cluster-level family-wise error-corrected P<0.05. Partial correlation analyses were performed in the PD-DR group to examine associations between susceptibility alterations in identified regions and drooling severity, after adjusting for age, sex, disease stage, and motor severity. Voxel-wise analysis revealed significantly increased susceptibility in the left superior temporal gyrus (STG) in the PD-DR group compared to the PD-NDR group (voxel-level P<0.001, cluster-level family-wise error-corrected P<0.05). In the PD-DR group, susceptibility values in the left STG showed a significant positive correlation with SCS-PD scores after adjusting for age, sex, Hoehn-Yahr stage, and Unified Parkinson's Disease Rating Scale Part III score (r=0.361, P=0.036). Compared to the HC group, the PD-DR group exhibited more widespread cortical susceptibility alterations. ROI analysis indicated higher susceptibility values in the left ventral pallidum (VP) and left parabrachial pigmented nucleus (PBP) in the PD-DR group compared to that in the HC group (Bonferroni-corrected P=0.042 and P=0.043, respectively). Furthermore, susceptibility values in the left PBP were significantly positively correlated with SCS-PD scores (r=0.506, P=0.002). Drooling in PD is associated with a distinct pattern of brain susceptibility alterations, supporting the involvement of a distributed neural network. Key regions include the left STG and the left PBP, which may be related to sensory integration, interoception, motivation, and motor control.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra, leading to debilitating motor and non-motor symptoms. Current therapeutic strategies, including levodopa, dopamine agonists, monoamine oxidase-B inhibitors, and surgical interventions primarily offer symptomatic relief without halting disease progression. Long-term use of these treatments is often associated with complications such as motor fluctuations, dyskinesia, and systemic side effects, underscoring the urgent need for safer and disease-modifying approaches. In recent years, increasing attention has been directed toward natural products as potential therapeutic agents for PD due to their multi-targeted mechanisms and favourable safety profiles. Among these, plant-derived saponins have emerged as promising candidates owing to their diverse pharmacological properties. Saponins exhibit potent antioxidant, anti-inflammatory, anti-apoptotic, and anti-aggregation activities, enabling them to modulate key pathological pathways involved in PD, including oxidative stress, mitochondrial dysfunction, neuroinflammation, and α-synuclein aggregation. Experimental studies have demonstrated the neuroprotective effects of various saponins such as astragaloside IV, ginsenosides, bacosides, dioscin, and notoginsenosides in animal models of PD. These compounds have been shown to preserve dopaminergic neuronal integrity, enhance mitochondrial function, regulate apoptotic signalling, and promote autophagy. Despite these promising findings, challenges such as poor bioavailability in natural sources and limited access to brain remain significant barriers to clinical translation. This review provides a comprehensive overview of current PD therapies and their limitations, while highlighting the therapeutic potential of plant-derived saponins as multi-target agents. It also discusses recent advances in drug delivery strategies that may enhance their clinical applicability. Overall, saponins represent a promising avenue for the development of novel neuroprotective and disease-modifying therapies for PD.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, characterized by the accumulation of α-synuclein (α-syn) aggregates and the loss of dopaminergic neurons in the midbrain. PD affects more than 10 million individuals worldwide, but no therapy has been proven to slow down its progression, posing a significant socioeconomic burden. Developing interventions to delay or halt disease progression remains a top priority for researchers. Recently, several disease-modifying approaches have been proposed for PD treatment, such as passive immunization, small-molecule inhibitors or gene editing therapy directly targeting α-syn aggregation, mitochondrial-targeted strategies, and cell replacement therapy. Our recent research has identified FAM171A2 as a novel neuronal receptor for pathological α-syn, offering a potentially viable target for disrupting α-syn transmission that is previously not known. Further development of these strategies could offer new hope for effective treatments of PD in the near future.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. While neuronal dysfunction has traditionally been the focal point of PD research, growing evidence highlights the critical roles of astrocytes - the most abundant glial cells in the central nervous system - in PD pathogenesis and therapy. Targeting astrocytes offers a promising therapeutic avenue through astrocyte-to-neuron reprogramming, inducing A2 phenotypic polarization, suppressing oxidative stress, modulating metal ion deposition, enhancing neurotransmitter homeostasis and promoting α-synuclein clearance. These diverse roles enable astrocytes to act as both protectors and potential contributors to disease progression, depending on the cellular environment. Furthermore, innovative strategies such as gene therapy, nanoparticle-based drug delivery, and astrocyte-derived exosome systems hold potential to overcome barriers like the blood-brain barrier and offer targeted, multifactorial interventions. Collectively, these findings advocate for a paradigm shift from a neuron-centric to a glia-inclusive framework in PD research and treatment, positioning astrocytes as central players in the quest for disease-modifying therapies.
Two major motor subtypes are widely recognized in Parkinson's disease (PD): tremor-dominant (TD) subtype and the postural instability-gait difficulty (PIGD) subtype. These distinct clinical phenotypes imply divergent underlying neural mechanisms. This study aimed to investigate the neural correlates of TD and PIGD subtypes using multiparametric analysis with hybrid positron emission tomography/magnetic resonance (PET/MR) and two tracers: [18F]-fluoropropyl-(+)-dihydrotetrabenazine ([18F]-AV133) and [18F]-fluorodeoxyglucose ([18F]-FDG). A total of 42 patients with PD (22 TD, 20 PIGD) and 27 healthy controls (HCs) were enrolled. Analysis of variance (ANOVA) and post hoc tests were performed to compare presynaptic dopaminergic function, cerebral glucose metabolism, and gray matter volume (GMV) across groups. Correlation analyses further explored relationships between imaging metrics and Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) scores. Receiver operating characteristic (ROC) curves were plotted. Relative to TD-PD patients, PIGD-PD patients showed significantly lower [18F]-AV133 binding in the bilateral putamen (contralateral anterior putamen: 1.72±0.33 vs. 2.05±0.56, P=0.033; ipsilateral anterior putamen: 1.57±0.38 vs. 1.82±0.40, P=0.044; contralateral posterior putamen: 1.69±0.40 vs. 1.43±0.17, P=0.011; ipsilateral posterior putamen: 1.37±0.14 vs. 1.55±0.33, P=0.030), with more symmetric dopaminergic impairment in the posterior putamen (0.09±0.11 vs. 0.19±0.17, P=0.025). PIGD-PD also exhibited reduced [18F]-FDG uptake in the lateral/medial prefrontal cortices (P=0.008 and 0.019), putamen (P<0.001), thalamus (P<0.001), pons (P<0.001), and cerebellum (P<0.001). Reduced GMV was noted in the bilateral cerebellum [(lobule IX, lobule IV/V) right lobule IX: P=0.035, left lobule IX: P=0.044, right lobule IV/V: P<0.001, left lobule IV/V: P<0.001], orbital superior frontal gyrus (right: P=0.007, left: P=0.003), postcentral gyrus (right: P=0.025, left: P<0.001), right cerebellar lobule VIII (P=0.048), left cerebellar lobule VIIb (P<0.001), left inferior temporal gyrus (P<0.001), and right thalamus (P=0.005). For PIGD-PD patients, correlation analyses revealed that bilateral putaminal [18F]-AV133 binding, prefrontal/putaminal [18F]-FDG uptake, and GMV in the orbital superior frontal gyrus, middle temporal gyrus, and cerebellum were significantly negatively correlated with UPDRS-III scores (r ranging from -0.833 to 0.607, all P<0.05). Multimodal integration achieved excellent discrimination [area under the curve (AUC) =0.923]. TD-PD and PIGD-PD exhibit distinct patterns of presynaptic dopaminergic dysfunction, cerebral hypometabolism, and gray matter atrophy. These neuroimaging differences may partially account for the divergent clinical manifestations between the two motor subtypes, Multimodal integration achieved excellent discrimination.
The substantia nigra (SN) is an emerging deep brain stimulation (DBS) target for Parkinson's disease (PD). However, its independent therapeutic profile remains obscured by concurrent subthalamic nucleus (STN) stimulation in clinical practice. We systematically evaluated the frequency-dependent efficacy, longitudinal feasibility, and clinical boundaries of direct SN DBS to optimize both targeted nigral modulation and STN-SN combined stimulation. Phase 1 comprised an acute randomized crossover assessment in which 30 participants underwent both SN stimulation at 10, 30, and 130 Hz and standard STN stimulation at 130 Hz. Outcomes included the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III), objective gait kinematics, and episodic memory. Phase 2 was an exploratory, non-randomized 3-month feasibility cohort. Seven participants initiated chronic SN stimulation; two discontinued because of treatment-limiting adverse events, and longitudinal outcomes were available for five treatment-tolerant completers, with descriptive comparison to five STN-DBS comparator participants. SN-DBS produced clear, frequency-dependent acute motor improvements. High-frequency (130 Hz) stimulation yielded the most pronounced clinical benefits, including a 43.6% reduction in MDS-UPDRS III and a 13.5% increase in stride length. The motor and spatial gait effects at 130 Hz were of similar magnitude to those observed with standard STN-DBS, while episodic memory performance remained stable across stimulation conditions. Patient-specific VTA mapping identified an outcome-associated region predominantly within the dorsal SN, and greater spatial overlap was associated with greater motor improvement. In Phase 2, chronic SN stimulation was maintained for 3 months in five of seven participants; two discontinued because of treatment-limiting adverse events. Direct SN stimulation produced a clear frequency-dependent acute response in PD, with 130 Hz yielding the strongest motor and spatial gait benefits among the tested frequencies and effects of similar magnitude to standard STN stimulation. VTA mapping localized the strongest response-associated region predominantly within the dorsal SN, and the 3-month observations provided a basis for further development of anatomically precise and individualized SN neuromodulation.
Mitochondrial dysfunction has been implicated in Parkinson's disease (PD), but the genetically regulated mitochondrial genes associated with PD risk remain incompletely defined. We conducted a summary-data-based genetic epidemiology study integrating summary-based Mendelian randomization (SMR), Heterogeneity in dependent instruments (HEIDI) filtering, and Bayesian colocalization to prioritize mitochondrial-related molecular features associated with PD risk. Mitochondrial-related genes were defined using MitoCarta3.0. Genetically predicted gene expression and plasma protein abundance were evaluated using expression quantitative trait loci (eQTL) data from eQTLGen and GTEx v8, and protein quantitative trait loci (pQTL) data was assessed using International Parkinson's Disease Genomics Consortium (IPDGC) as the discovery genome-wide association study (GWAS) and FinnGen as the replication dataset. Prespecified QTL analyses were interpreted using FDR correction, HEIDI filtering, and colocalization support. DNA methylation QTL analysis, mitochondrial phenotype MR, and single-nucleus RNA-seq analysis were performed as complementary analyses. In the primary eQTL analysis, higher genetically predicted TTC19 expression was associated with lower PD risk (OR = 0.80, 95% CI: 0.74-0.87, PPH4 = 0.80), whereas higher MALSU1 expression was associated with increased PD risk (OR = 2.21, 95% CI: 1.59-3.06, PPH4 = 0.96). Both associations survived FDR correction, passed HEIDI filtering, and showed colocalization support. GTEx whole-blood data supported the direction of the TTC19 association. No mitochondrial protein reached significance after FDR correction and colocalization filtering in the primary pQTL analysis. Complementary methylation analysis highlighted cg06270993 as an exploratory regulatory signal for MALSU1. This MR-colocalization study prioritizes TTC19 and MALSU1 as genetically supported mitochondrial-related candidate genes associated with PD risk. Further validation is required to define their functional roles in PD pathogenesis.
Pain is a highly prevalent and disabling non-motor symptom of Parkinson's disease (PD), yet it remains underrecognized and frequently undertreated in clinical practice. Although long considered a secondary consequence of motor dysfunction, pain in PD is now increasingly understood as a manifestation of disease-related alterations in nociceptive processing. These changes extend beyond dopaminergic deficiency and involve broader neurotransmitter imbalances and impaired descending inhibitory control across different neuroanatomical regions, providing a framework for understanding pain as an intrinsic feature of PD rather than a purely peripheral or motor-related phenomenon. We also summarize the main categories of pain experienced in PD, each with distinct clinical features and underlying pathophysiological mechanisms, and link them with current management strategies. A multimodal, mechanism-informed approach that integrates optimization of dopaminergic therapy with non-dopaminergic pharmacological treatments, neuromodulation, rehabilitation, and complementary interventions is key to a personalized treatment plan for pain in patients with PD. Finally, we highlight emerging translational directions, including candidate biomarkers that may help objectify pain and its related dysfunction in the PD population. Focusing on the neurobiological basis of pain in PD, this review aims to support a shift toward mechanism-based assessment and management, with an ultimate goal of improving pain outcomes and quality of life for individuals living with the disease.
Objectives The Unified Parkinson's Disease Rating Scale (UPDRS Part III), is often not obtained post-operatively in routine clinical practice, limiting objective assessment of treatment response following deep brain stimulation (DBS). Natural language processing (NLP) offers a potential approach to use narrative clinical documentation to predict motor outcomes and evaluate therapeutic responsiveness when formal post-operative scoring is unavailable. Methods Neurology notes and UPDRS Part III assessments were obtained from 25 patients with Parkinson disease (PD) pre- and post-operatively. DBS response was defined as percent improvement in UPDRS Part III from the pre-operative OFF-medication state to the post-operative DBS/medication ON assessment. We assessed whether UPDRS Part III scores could be predicted from clinic notes and whether improvement could be predicted from pre-operative notes. Four NLP approaches were evaluated: TF-IDF with linear models, BERT-base, ClinicalBERT, and Bio-ClinicalBERT embeddings. Models were assessed using leave-one-out cross-validation, with performance evaluated using mean absolute error, coefficient of determination (R²), Spearman correlation, and area under the ROC curve. Results All approaches differentiated pre-operative notes from post-operative notes. The TF-IDF model demonstrated moderate accuracy at predicting UPDRS Part III total scores and percentage change. Several individual motor subscores demonstrated significant correlations between predicted and observed values, including tremor, rigidity, and limb agility measures. Tremor-dominant and rigidity-bradykinesia phenotypes were associated with lower prediction error, whereas the PIGD phenotype showed increased error when predicting postoperative motor improvement. Conclusions These findings support the feasibility of using NLP to detect signal in routine DBS clinical documentation, but they should be interpreted as exploratory. NLP-derived outputs may complement, but should not replace, formal UPDRS-III assessment.
Parkinson's disease (PD) research traditionally relies on animal models and two-dimensional (2D) culture models. These models fail to recapitulate the complex cellular architecture and network interactions that are possible with three-dimensional (3D) organoid models. While 3D models allow improved cell-cell interactions, spatial organization, and metabolic microenvironments, however, their utility for modelling dopaminergic neurodegeneration remains underexplored. We developed and characterized 3D organoids from LUHMES cells which are human embryonic neuronal precursor cells and a well-established human dopaminergic neuronal cell line. We directly compare their responses to the mitochondrial toxin MPP+ against conventional 2D cultures. Functional readouts included cell viability, ATP production, dopaminergic marker expression (tyrosine hydroxylase, MAP2, β-III tubulin), reactive oxygen species (ROS) generation, electrophysiological activity via multi-electrode arrays (MEA), and calcium signalling dynamics. 3D LUHMES organoids had 9-fold higher synapsin expression compared to 2D cultures, indicating enhanced synaptic maturity and network complexity. Following acute MPP+ exposure (0.25 mM, 24 h), 3D organoids were significantly more sensitive than 2D cultures, with greater reductions in cell viability (35% vs. 31%), ATP production (36% vs. 31%), and dopaminergic marker expression (TH: 60% reduction in both; MAP2: 70% vs. 54%; TUJ1: 62% vs. 20%). ROS production increased uniformly in 3D organoids (85% positive cells) compared to heterogeneous accumulation in 2D cultures (78% positive cells). Functional assessments revealed that 3D organoids displayed higher baseline electrophysiological activity that was sensitive to impairment following MPP+ treatment, spike amplitude, and calcium signalling responses to various stimuli (ATP, glutamate, GABA). LUHMES-derived 3D organoids demonstrate greater physiological relevance for modelling PD-related dopaminergic neurodegeneration than 2D cultures. The enhanced sensitivity to mitochondrial toxins, combined with more sophisticated network architecture and functional properties, suggests this model is a valuable platform for mechanistic studies of neurodegeneration and preclinical drug screening. These findings also support the broader adoption of 3D culture systems in neurodegenerative disease research.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons, oxidative stress, mitochondrial dysfunction, and metabolic imbalance. These pathological processes alter cellular biochemical composition and may generate detectable spectral signatures. In the present study, Fourier transform infrared (FT-IR) spectroscopy was employed to investigate biochemical alterations associated with neurotoxicant-induced PD phenotypes in Drosophila melanogaster. PD-like phenotypes were induced using paraquat, rotenone, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and were validated through locomotor impairment and dopaminergic neuronal degeneration. Spectra (400-4000 cm-1) revealed characteristic alterations within lipid (2800-3000 cm-1), protein amide (∼1650 and ∼ 1540 cm-1), and fingerprint regions indicating modifications in macromolecular composition following neurotoxic exposure. Principal component analysis (PCA) and hierarchical clustering revealed intrinsic spectral differences between control and treated groups, while partial least squares discriminant analysis (PLS-DA) supported group discrimination, with permutation testing indicating that the observed separation was unlikely to arise by chance. Variable importance in projection (VIP) analysis identified prominent contributions from fingerprint and lipid-associated spectral regions, particularly within the 1012-1040 cm-1 domain. Classification models (KNN, RF) further supported robust separation between control and PD groups using independent test datasets. The observed spectral alterations were consistent with independent biological evidence of oxidative stress, mitochondrial dysfunction, lipid accumulation, and neurodegeneration. Together, these findings demonstrate that ATR-FTIR spectroscopy provides a rapid, label-free, and biologically informative approach for characterizing PD biochemical alterations and highlight its potential application in neurodegenerative disease research and neurotoxicity assessment.
Physical activity is associated with better clinical outcomes in Parkinson's disease (PD). This study aimed to investigate the effects of physical activity on longitudinal changes in dopamine transporter (DAT) availability and motor and cognitive outcomes. Additionally, it explored whether striatal dopaminergic integrity mediates these effects. Using data from the Parkinson's Progression Markers Initiative, we included patients with PD who had at least 4 years of follow-up data on the Physical Activity Scale for the Elderly and at least two assessments of DAT imaging, motor and cognitive functions, resulting in three analytical datasets (n = 141, 233, and 259, respectively). Linear mixed-effects models were used to analyse the influence of physical activity on the progression of DAT availability and clinical outcomes. Multilevel mediation analyses investigated the mediation effect of physical activity on the rate of clinical progression. Higher levels of physical activity were significantly associated with a slower decline in caudate DAT availability, attenuated progression of axial symptoms, rigidity, and overall motor severity, and better preservation of Montreal Cognitive Assessment and Symbol Digit Modalities Test scores. Mediation analyses demonstrated that higher physical activity was significantly associated with slower caudate DAT decline; however, none of the clinical outcomes were significantly mediated by caudate DAT preservation, as all indirect effects were non-significant. These findings suggest that physical activity is associated with both dopaminergic degeneration and clinical progression in PD. However, the observed clinical benefits are likely primarily driven by mechanisms beyond striatal dopaminergic preservation.
Parkinson's disease (PD) is second only to Alzheimer's disease as the most common human neurodegenerative disorder. Despite intense investigation, no interdictive therapy is available for PD. Recent studies indicate that both innate and adaptive immune processes are active in PD. Accordingly, we found rapid increase in RANTES (regulated on activation, normal T cell expressed and secreted) and eotaxin, chemokines that are involved in T cell trafficking, in vivo in the substantia nigra pars compacta (SNpc) and the serum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. RANTES and eotaxin were also upregulated in the SNpc of postmortem PD brains as compared to age-matched controls. Therefore, we investigated whether neutralization of RANTES and eotaxin could protect against nigrostriatal degeneration in MPTP-intoxicated mice. Interestingly, after peripheral administration, functional blocking antibodies against RANTES and eotaxin reduced the infiltration of CD4+ and CD8+ T cells into the nigra, attenuated nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. Therefore, we conclude that attenuation of chemokine-dependent adaptive immune response may be of therapeutic benefit for PD patients.
Neurodegenerative diseases represent a major global public health challenge, imposing substantial societal and economic burdens. Their complex pathogenesis and limited therapeutic options underscore an urgent need for new paradigms. Emerging evidence indicates that dysregulation of the brain's immune microenvironment is a critical driver of disease progression. Conventional wisdom posits that peripheral immune cells and central glial cells serve as the primary initiators of neuroimmune responses, whereas neurons are regarded merely as passive recipients of inflammatory damage. Emerging evidence suggests that upon receiving pathological signals in the central nervous system, neurons may become more vulnerable and participate in the onset of neuroimmune processes, positioning them as potential targets for early intervention in neurodegenerative diseases. This article systematically reviews the contribution of neuron-derived immune-inflammatory responses in neurodegenerative diseases and potential intervention strategies. We first outline the capacity of neurons to regulate neuroimmune responses and detail the underlying molecular mechanisms. Then we compare the specific mechanisms by which neurons with different susceptibility drive and amplify neuroinflammation in various neurodegenerative diseases such as alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, vascular cognitive impairment, and transformed these mechanisms into intervention strategies targeting neurons,. This article aims to break through the traditional concept of passive neuronal damage, systematically integrate intervention strategies that shift from targeting peripheral immune and glial cells to regulating neuron-derived immunity, thereby providing a new theoretical framework for overcoming current clinical limitations and identifying effective therapeutic targets for the prevention and treatment of neurodegenerative diseases.