Parkinsonian Features Research Articles (Page 1)

Symptom onset lateralization and bilaterality in Parkinson's disease: Clinical implications of motor and non-motor profiles.

Unlocking molecular secrets: The role of miRNAs in Parkinson's disease dynamics.

Lead (Pb) exposure is strongly associated with neurodegenerative diseases such as Parkinson's disease (PD). A prominent pathological feature of PD is the degeneration of dopaminergic (DA) neurons. However, the molecular mechanisms underlying Pb-induced DA neuron loss have been insufficiently explored. This study investigated these mechanisms using both in vitro DA neuron cell models and in vivo fly models, demonstrating that ferroptosis is the primary driver of Pb-induced DA neuron death. Mechanistically, Pb2+ directly bound to Glu-486/Glu-316 residues of System Xc-, inhibiting SLC7A11-mediated cystine uptake and depleting glutathione (GSH), thereby triggering ferroptosis. Notably, differentiated DA neurons exhibited heightened sensitivity to Pb-induced ferroptosis, as their cystine uptake was more readily inhibited by Pb exposure than that in mature neurons. These in vitro findings were corroborated in fly models, where Pb exposure during the larval stage resulted in more pronounced PD phenotypes compared with exposure during the adult stage. Notably, administration of GSH precursor alleviated these PD phenotypes in DA neuron numbers and behavior with more effective rescue observed in the larval stage. Consequently, our findings provide crucial data for developing future strategies to mitigate environmental Pb exposure and prevent PD.

Parkinson's disease (PD) has been associated with alterations in neuronal activity in the basal ganglia-thalamocortical (BGTC) network. Previous studies have suggested that cortical disinhibition is a feature of PD, but there has been little direct evidence of the changes in cortical neuronal spiking activity to support this hypothesis. To test the hypothesis that activity in the motor cortex is enhanced in PD, we investigated the effects of parkinsonism on movement-related neuronal activity in the primary motor cortex (M1). Microelectrode arrays were chronically implanted in M1 of two nonhuman primates and populations of cells were collected before and after the induction of parkinsonism using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In both animals, we found that during the reaching task in the parkinsonian state, the proportion of M1 neurons that were activated (excited) during movement were increased, while those that were suppressed (inhibited) decreased. These data support the concept that dopaminergic loss in parkinsonism promotes a loss of inhibition in the motor cortex, leading to overactivity in M1 and a disruption in spatial-temporal processing of information within the BGTC circuit that contributes to the motor dysfunction observed in PD.

Blood-based RNA transcriptomics offers a promising avenue for identifying biomarkers of Parkinson’s disease (PD) progression and mechanisms of pathogenesis. Previous work uncovered an age-related increase of neutrophil-enriched gene expression in PD whole blood, which may obscure disease-relevant transcriptomic signals. To better capture PD-associated molecular differences, we analyzed PD whole-blood RNA sequencing data using a differential expression approach that accounts for neutrophil composition. We built a model to estimate neutrophil percentages in 6897 Parkinson’s Progression Markers Initiative and Parkinson’s Disease Biomarkers Program samples from gene expression. By incorporating predicted neutrophil percentages as a covariate, we see significant SNCA downregulation in all PD cohorts, a signal previously obscured by immune cell-related effects. Lowered SNCA expression was observed in individuals with known PD-linked gene mutations (e.g., SNCA, GBA1, LRRK2) and those without known pathogenic variants. These findings suggest that decreased SNCA expression in whole blood may be a defining transcriptomic feature of PD.

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, remains without a curative pharmacological intervention. Sea Cucumber Peptides (SCP) are recognized for their antioxidant properties and neuroprotective potential, while no specific SCP have been documented for PD treatment. Moreover, sea cucumbers have long been consumed as a traditional food; viewed through the lens of "food-medicine homology", their peptides possess clear pharmaceutical potential. This study sets out to pinpoint particular peptide sequences from sea cucumbers could combat PD, exploring their therapeutic efficacy and the underlying mechanisms. We treated Rotenone (Rot)-induced C57BL/6 J mice and SH-SY5Y cells with the SCP which were extracted from the sea cucumbers, to assess the impact on behavioral metrics in mice, histopathological outcomes, cellular viability, and in vitro bioactivity. Employing a combination of peptide profiling and silico analysis, we established a SCP spectrum to identify novel SCP with potential anti-PD activity. The therapeutic effects and mechanisms of the peptides were further investigated in 7-day-old zebrafish larvae and SH-SY5Y cells exposed in Rot, respectively. Our findings indicate that the SCP significantly improved behavioral deficits in mice, reduced the degeneration of dopaminergic neurons in the substantia nigra, and increased the survival of Rot-exposed SH-SY5Y cells. Notably, a novel peptide, Gln-Trp-Phe-Asp-Trp (QWFDW), emerged from our peptide profiling and in silico analysis, showing significant anti-PD activity. QWFDW was demonstrated to enhance the behavioral performance of Rot-induced zebrafish larvae, and ameliorate the pathological features of PD by attenuating endogenous reactive oxygen species (ROS) and maintaining mitochondrial membrane potential in SH-SY5Y cells. At the cellular level, QWFDW activates the Nrf2/HO-1/GPX4 pathway to alleviate ferroptosis and exert therapeutic effects on PD. Collectively, our results point out that SCP, particularly QWFDW, was a prospective therapeutic agent for PD.

Parkinson's disease (PD) ranks as the second most prevalent neurodegenerative condition affecting individuals in their middle age and beyond. Its hallmark features include the abnormal accumulation of α-synuclein protein and the progressive loss of dopaminergic neurons. A substantial body of evidence supports the notion that an imbalance in the gut microbiome, known as dysbiosis, contributes to the misfolding and accumulation of α-synuclein, a key pathological feature of PD. This finding raises the possibility that restoring the gut microbiome, particularly the bacteria associated with α-synuclein, could serve as a promising therapeutic approach for PD. There is evidence that β-glucan can play an important role in the reconstitution of gut microbiome. In this regard, this study reviews the evidence showing the role of β-glucan in reducing α-synuclein accumulation and mitigating the progression of PD. This scooping review study presents promising prospects for advancing novel therapeutic approaches to benefit individuals with PD.

Background: Parkinson’s disease (PD) is a neurodegenerative disorder for which no curative therapies currently exist. Experimental models employing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reproduce PD features such as striatal dopaminergic dysfunction and motor deficits. Various MPTP dosing regimens are used to screen drug candidates for PD, but their validity is limited because of the predominant use of young male animals. Sex bias is another issue that is underrepresented in PD research, since females are more susceptible to this pathology. Here, we studied the model of bolus administration of MPTP (30 mg/kg) in aged female mice and assessed its sensitivity to the antioxidants fullerene C60 and fullerenol C60(OH)24, given that oxidative stress is a key contributor to PD. Methods: 12-month-old female C57BL/6 mice received fullerene (0.1 mg/kg/day, via diet) or fullerenol (0.15 mg/kg/day, via drinking water). On day 10, mice were injected with MPTP. We studied tremor, piloerection, and behavior in the pole test, rotarod, pole test, and open field. High-performance liquid chromatography (HPLC) was employed to study dopaminergic neurotransmission, and the expression levels of its molecular regulators and nitric oxide synthase (NOS)-related targets were investigated using RT-PCR in the striatum and cortex. Results: MPTP-challenged mice displayed profound impairment in markers of dopaminergic neurotransmission and cellular distress, and showed disrupted motor behavior and vegetative functions. Antioxidant-treated animals that received a bolus injection of MPTP demonstrated partial preservation of tremor response, dopaminergic parameters, and iNOS and nNOS gene expression, although motor performance in the pole test was only modestly improved. Fullerenol appeared more effective in decreasing MPTP-induced neurochemical changes. Conclusions: The applied MPTP model showed its validity in mimicking PD features and was sensitive to low doses of antioxidants, suggesting its usefulness for screening drugs that target oxidative and nitrosative stress. The neuroprotective effects of fullerene-based compounds suggest their potential utility in the treatment of PD.

Microglia-drive IRF8 upregulates complement pathway in Parkinson's disease.

The glymphatic system is instrumental in cerebral waste drainage, and its impairment is mechanistically linked to the pathogenesis of neurodegenerative diseases like Parkinson's disease (PD). Nevertheless, the relationship between dysfunction in the clearance processes and the intensity of motor symptoms in PD remains inadequately characterized. This study applied the non-invasive Diffusion Tensor Image Analysis along the Perivascular Space technique to quantify the clearance network activity in PD patients compared with healthy controls (HCs), probing its prospects as an imaging biomarker for motor impairment. From January 2024 to June 2025, a total of 43 PD patients, diagnosed according to the clinical diagnostic criteria, along with 31 well-matched HCs, were enrolled. All participants underwent MRI, and the waste-clearance system function was evaluated using the DTI-ALPS index. Motor manifestations in the PD group were systematically rated using the MDS-UPDRS. An independent sample t-test was carried out to compare the disparities in this imaging metric between groups. Correlation and multiple regression analyses were further employed to explore the connections between the imaging metric and parkinsonian motor features. This study demonstrated a significantly lower MRI-derived metric in the PD group (1.19 ± 0.14) relative to HCs (1.27 ± 0.13; p = 0.019). The statistical significance of this difference persisted after covariance adjustment for age, years of education, and drinking history via ANCOVA (B = 0.080, 95% CI [0.015, 0.145], p = 0.016). Pearson correlation analysis revealed significant inverse associations between this radiographic measure and both the total MDS-UPDRS score (r = -0.418, p = 0.005; Bootstrap 95% BCa CI [-0.628, -0.171]) and its motor subsection (Part III) score (r = -0.424, p = 0.005; Bootstrap 95% BCa CI [-0.644, -0.169]). Multiple regression indicated that the imaging metric served as an independent negative predictor of motor symptom severity (standardized β = -0.420, p = 0.010; B = -42.45, Bootstrap 95% BCa CI [-79.17, -9.91]), accounting independently for 14.6% of the variability in motor severity (ΔR2 = 0.146, p = 0.008). These results suggest an association between the imaging metric and the function of the clearance network in PD, as well as a significant correlation with motor disability. These findings warrant further investigation into the metric's potential as a neuroimaging marker for motor impairment.

Parkinson's disease (PD) is characterized by a combination of motor and non-motor symptoms, which can fluctuate over time. Recognition of nonmotor fluctuations (NMF) as a distinct and relevant feature of PD is recent, and their impact on patients' health-related quality of life (HRQoL) and on caregivers' burden remains underexplored. This study aimed to evaluate the effect of NMF on patients' HRQoL and caregiver burden, and to compare it with the impact of motor complications (MC). Patients and caregivers were consecutively recruited from five Italian Movement Disorder centers. Assessments included the Non-Motor Fluctuation Assessment, the MDS-sponsored Unified PD Rating Scale, the Mini-Mental State Examination, the 39-item Parkinson's Disease Questionnaire (PDQ-39), and the Zarit Burden Interview (ZBI). Linear regression analyses examined associations between total NMF and MC scores with PDQ-39 and ZBI. Logistic regression estimated the odds of moderate-severe caregiver burden based on NMF. 149 patients and 135 caregivers were included. Higher NMF scores were associated with worse HRQoL (PDQ-39: Beta = 0.318; p < 0.001), and correlated with most PDQ-39 domains, excluding stigma. MC also correlated with PDQ-39-(Beta = 0.338; p < 0.001), particularly in domains such as mobility, ADLs, communication, and bodily discomfort. Both NMF and MC scores were associated with caregiver burden (ZBI: Beta = 0.374 and 0.437, respectively; p < 0.001). Each additional NMF point increased the odds of caregiver burden by 11.6% (OR = 1.116, 95% CI:1.043-1.194, p < 0.001). NMF significantly affect both patient HRQoL and caregiver burden, with an impact comparable to that of MC. Systematic assessment and targeted interventions for NMF should be integrated into routine PD care.

Parkinson’s disease (PD), the second most common neurodegenerative disorder globally, has a notably high prevalence in Sweden (136/105). Although monogenic forms represent only a small subset of PD cases, several genetic factors—including nucleotide repeat expansions (NREs) in ATXN2, ATXN3, C9ORF72, TBP, POLG, TOMM40, CACNA1A, and PRNP—have been implicated in neurodegenerative conditions with parkinsonian features. However, their contribution to PD pathogenesis in the Swedish population remains understudied. We analyzed DNA from 161 Swedish PD patients and 546 controls and evaluated clinical and CSF biomarkers (tau, phospho-tau, and β-amyloid). Intermediate ATXN2 CAG expansions were significantly associated with PD (3.40%, p = 0.0027), and novel promoter structural variations were identified. C9ORF72 G4C2 expansions were also linked to PD (2.48%, p = 0.0018), with distinct methylation patterns in PD cases. POLG Not-10/Not-11Q alleles were positively associated (9.62%, p = 0.014), while TOMM40 showed partial associations for rare genotypes (14.28%, p = 0.0014). Pathological expansions in TBP were marginally significant, while ATXN3, CACNA1A, and PRNP showed no associations. Two-way ANOVA identified significant interactions between APOE E3/E4 and POLG 10/11Q genotypes, affecting age at diagnosis (p = 0.025) and CSF β-amyloid levels. Regression highlighted tau as a key predictor of age at diagnosis (p = 0.02). Longitudinally, APOE E4 predicted cognitive decline (p = 0.015), and TOMM40 haplotypes correlated with motor deficits. In conclusion, ATXN2, C9ORF72, and POLG emerge as key genetic risk factors for PD in the Swedish population, with TOMM40 and TBP contributing partially. Altered CSF biomarker patterns support the existence of distinct molecular subtypes and warrant further investigation of novel ATXN2 variants as potential PD modifiers.

Parkinson’s disease (PD) is characterized by the selective degeneration of midbrain dopaminergic neurons and aggregation of α-synuclein. Emerging evidence implicates the gut microbiome in PD, with microbial metabolites proposed as potential pathological mediators. However, the specific microbes and metabolites involved, and whether gut-derived metabolites can reach the brain to directly induce neurodegeneration, remain unclear. Here we show that elevated levels of Streptococcus mutans (S. mutans) and its enzyme urocanate reductase (UrdA), which produces imidazole propionate (ImP), in the gut microbiome of patients with PD, along with increased plasma ImP. Colonization of mice with S. mutans harboring UrdA or Escherichia coli expressing UrdA from S. mutans increases systemic and brain ImP levels, inducing PD-like symptoms including dopaminergic neuronal loss, astrogliosis, microgliosis, and motor impairment. Additionally, S. mutans exacerbates α-synuclein pathology in a mouse model. ImP administration alone recapitulates key PD features, supporting the UrdA–ImP axis as a microbial driver of PD pathology. Mechanistically, mTORC1 activation is crucial for both S. mutans- and ImP-induced PD pathology. Together, these findings identify microbial ImP, produced via UrdA, as a direct pathological mediator of the gut-brain axis in PD.

Parkinson's disease (PD) is a complex multifactorial disorder with a genetic component in about 15% of cases. Multiplications and point mutations in SNCA gene, encoding α-synuclein (aSyn), are linked to rare familial forms of PD. Our goal was to assess the clinical presentation and the biological effects of a novel K58N aSyn mutation identified in a patient with PD. We describe the clinical presentation associated with the novel mutation, together with genetic testing through whole exome sequencing (WES). Furthermore, we conducted extensive biophysical and cellular assays to assess the functional consequences of this novel variant. The patient exhibited typical features of sporadic PD with early onset and a benign disease course. WES showed a novel heterozygous missense variant in SNCA (NM_000345.4, c.174G>C; p.K58N). A positive family history of PD was evident, because both a parent and a grandparent had been diagnosed with PD but were deceased. The patient underwent deep brain stimulation surgery 13 years postdiagnosis, showing stable, long-term improvements in motor symptoms. Biophysical studies demonstrated K58N substitution causes local structural effects, disrupts membrane binding, and enhances aSyn in vitro aggregation. In cellular systems, K58N aSyn produces fewer inclusions per cell and does not form condensates. The variant increases aSyn cytoplasmic distribution and displays aberrant activity-dependent dynamic serine-129 phosphorylation. The clinical presentation associated with the novel K58N aSyn mutation suggests a relatively benign PD course consistent with the phenotypic spectrum of idiopathic PD. Overall, our molecular studies provide novel insight into the biology and pathobiology of aSyn. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neurodegenerative diseases are classified based on their histopathological hallmarks alongside their clinical manifestations. Alzheimer’s disease and Lewy body disease, which includes Parkinson’s disease, are traditionally referred to as tauopathy and synucleinopathy, respectively. However, much like how Alzheimer’s disease can present with Parkinsonian features and Parkinson’s disease with cognitive impairment, there is considerable overlap in their underlying pathology. In this study, we applied antibodies specific for disease-related, post-translationally modified epitopes in α-synuclein and tau to post-mortem brain tissue from 16 Alzheimer’s disease and 9 Lewy body disease cases with a focus on the substantia nigra and the locus coeruleus. We demonstrate the presence of inclusion pathology comprised of carboxy-terminally truncated α-synuclein in the substantia nigra and locus coeruleus of Alzheimer’s disease cases that is not revealed with standard post-mortem screening. These findings suggest that α-synuclein pathology in Alzheimer’s disease can be significantly underestimated. Additionally, we observed abundant tau pathology in the substantia nigra of Alzheimer’s disease cases at levels often exceeding those seen in Lewy body disease, despite the absence of a movement disorder diagnosis in Alzheimer’s disease cases. Furthermore, the connection between regional tau pathology and associated clinical impairment may be region-dependent, where some tau pathology may be, at least temporally, innocuous.

A double-blind, controlled trial of circadian effective light therapy in patients with Parkinson's disease.

Eye blinking characteristics as potential biomarkers in Isolated REM sleep behavior disorder during visuospatial attention tasks.

Pick's disease presenting as progressive apraxia of speech: Atypical clinical and neuroimaging features in three autopsy-confirmed cases.

Background: Parkinson’s disease (PD) is a neurodegenerative disorder with a complex aetiology involving several genetic and environmental factors. Although no clear evidence of a direct link between the electronic features of DNA and PD has been found, elucidating the role of DNA in cellular function and dysfunction could provide valuable insights into the mechanisms of the disease (e.g. mutations occurring in the phosphatase and tensin homolog [PTEN]-induced kinase 1 [PINK1] DNA of PD). This study aimed to analyse topographic images and measure the electronic conductivity of synthetic normal and mutant PINK1 DNA molecules. Methods: Two 15-mer synthetic oligonucleotides of Oligo1 normal PINK1 (5’-CAG CTG CTG GAA GGC-3’) and Oligo2 mutant PINK1 (5’-CAG CTG CCG GAA GGC-3’) were measured using scanning tunnelling microscopy and spectroscopy. Results: The study’s findings revealed that the mean values of the voltage gap (Vg) between Oligo1 normal and Oligo2 mutant PINK1 DNA molecules at the mutation region A2–C2 are 1.204 ± 0.198 V and 0.676 ± 0.495 V, respectively, indicating differences in the electronic properties between the Oligo1 normal and Oligo2 mutant PINK1 DNA molecules. However, the mean Vg values of Oligo1 normal and Oligo2 mutant PINK1 DNA molecules were found to not significantly differ from each other (P = 0.162 &gt; ? = 0.05). Conclusion: The study found that the voltage gap between normal and mutant PINK1 DNA molecules is not significantly different, suggesting that DNA sequence differences may not directly alter electrical properties. However, PINK1 mutations play a role in early-onset PD due to mitochondrial dysfunction, and future therapies should focus on restoring PINK1-Parkin signalling and mitochondrial health.

Dural arteriovenous fistulas (DAVFs) are abnormal arteriovenous shunts that occur between intracranial arteries and venous sinuses, meningeal veins, or cortical veins. These lesions can lead to pathological changes such as cerebral edema, increased intracranial pressure, metabolic dysfunction in the brain, venous sinus thrombosis, and vascular rupture with hemorrhage. Clinically, DAVFs rarely present as Parkinsonism, often coexisting with dementia. While there are numerous global reports of DAVF with cognitive impairment as the primary symptom, cases of DAVF presenting predominantly with Parkinsonism are exceedingly rare. Secondary Parkinsonism in DAVF may be associated with deep venous reflux and venous hypertension involving the basal ganglia. Severe dementia symptoms may overshadow Parkinsonian features, complicating the clinical diagnosis of DAVF-induced Parkinsonism. This article aims to review published case reports and series to summarize the clinical and imaging characteristics (CT, MRI, and angiography) of these patients, evaluate the quality of the cases, and hypothesize potential pathophysiological mechanisms, providing clinical guidance for the management of DAVF-associated Parkinsonism.