Parkinson's Disease Patients Research Articles

Comprehensive data for studying serum exosome microRNA transcriptome in Parkinson’s disease patients

Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder, was classically attributed to alpha-synuclein aggregation and consequent loss of dopaminergic neurons in the substantia nigra pars compacta. Recently, emerging evidence suggested a broader spectrum of contributing factors, including exosome-mediated intercellular communication, which can potentially serve as biomarkers and therapeutic targets. However, there is a remarkable lack of comprehensive studies that connect the serum exosome microRNA (miRNA) transcriptome with demographic, clinical, and neuroimaging data in PD patients. Here, we present serum exosome miRNA transcriptome data generated from four cohort studies. Two of these studies include 96 PD patients and 80 age- and gender-matched controls, with anonymised demographic, clinical, and neuroimaging data provided for PD patients. The other two studies involve 96 PD patients who were evaluated both before and after one year of treatment with rasagiline, a widely prescribed anti-parkinsonism drug. Together, the datasets provide a valuable source for understanding pathogenesis and discovering biomarkers and therapeutic targets in PD.

Validation Study of the Parkinson's Disease Stigma Questionnaire (PDStigmaQuest).

Stigma is a relevant aspect of Parkinson's disease (PD). Specific stigma tools are needed to address the complex construct of stigma in PD comprehensively. To test the dimensionality and psychometric properties of the newly developed Parkinson's Disease Stigma Questionnaire (PDStigmaQuest). In this multi-center, cross-sectional study including PD patients and healthy controls, the dimensionality of the PDStigmaQuest was examined through exploratory factor analysis. Acceptability and psychometric properties were investigated. PDStigmaQuest scores of patients and healthy controls were compared. In total, 201 PD patients and 101 healthy controls were included in the final analysis. Results suggested high data quality of the PDStigmaQuest (0.0001% missing data for patients). The exploratory factor analysis produced four factors: felt stigma, hiding, enacted stigma: rejection, and enacted stigma: patronization, explaining 47.9% of variance. An optional work domain for employed patients was included. Moderate floor effects and skewness, but no ceiling effects were found. Cronbach's alpha of 0.85 indicated high internal consistency. Calculated item-total correlations met standard criteria. Test-retest reliability was high (rs = 0.83). PDStigmaQuest scores correlated significantly with other stigma measures (rs = 0.56-0.69) and were significantly higher in patients than in healthy controls and higher in patients with depressive symptoms than in those without. The patient-reported 18-item PDStigmaQuest showed strong psychometric properties of validity and reliability. Our results suggest that the PDStigmaQuest can be used to assess and evaluate stigma comprehensively in PD, which will improve our understanding of the construct of PD stigma.

Modulation of Cerebellar Oscillations with Subthalamic Stimulation in Patients with Parkinson's Disease.

Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) has emerged as a potent treatment for alleviating motor symptoms in Parkinson's disease (PD). Despite its effectiveness, the impact of high frequency STN-DBS on cerebellar oscillations remains unclear, posing an intriguing challenge for neural modulation. Given the direct and indirect connections between the STN and cerebellum, we investigated whether STN-DBS affects cerebellar oscillations. To observe the effects of STN-DBS on cerebellar oscillations in patients with PD. We recruited 15 PD patients receiving STN-DBS. Electroencephalographic (EEG) signals were recorded from cerebellar regions during resting-state conditions in both the OFF-DBS and STN-DBS conditions. Our analyses centered on spectral features, particularly theta and beta oscillations, guided by prior research and correlation tests to investigate the relationship between oscillatory changes and motor symptom severity. In the mid-cerebellar (Cbz) region, we observed a significant increase in the relative power in all frequency bands, including theta and beta oscillations during STN-DBS, showing the global effect of DBS. Importantly, the correlation results indicated significant associations between mid-cerebellar (Cbz) beta power during the OFF condition and motor severity, which were not evident during STN-DBS. Interestingly, correlations between beta power and motor severity were not observed at the mid-occipital (Oz) and mid-frontal (Cz) regions. Notably, signal similarity analyses demonstrated no evidence of volume conduction effects between the mid-cerebellar (Cbz) and nearby mid-occipital (Oz) regions. While these findings provide valuable insights into the complex interplay between STN-DBS and neural oscillations, further research is essential to decipher their precise functional significance and clinical implications. Understanding these intricacies may contribute to the optimization of DBS therapies for PD.

Japanese Mucuna pruriens (Hasshou Beans) Showed Fast-acting and Long-lasting Effects in Parkinson's Disease.

Objective Mucuna pruriens (MP) is a legume whose seeds contain levodopa (LD), which has potential therapeutic effects against Parkinson's disease (PD). However, further research is needed to thoroughly evaluate its efficacy and safety for treating this condition. In this study, we analyzed the pharmacokinetics of MP grown in Japan and investigated its mechanism of action in PD. Methods MP seeds ground after roasting (containing 4.02% LD per MP powder) were used as the reagent and compared with an equivalent LD/carbidopa (CD) preparation. This clinical trial was conducted using a crossover design among PD patients attending our institution. Each patient received a single dose of 100/10 mg LD/CD tablets and 11 g of MP reagent. Results Among the seven patients with PD, MP prolonged the ON time 2-fold compared to LD/CD. The LD concentrations after MP intake were higher than those after LD/CD intake, whereas dyskinesia did not increase. An analysis of the LD metabolites showed that the 3-O-methyl-dopa/LD metabolic ratio was significantly lower after MP ingestion than after LD/CD ingestion, indicating that MP has a catechol-O-methyl transferase inhibitory effect. Conclusions This is the first report of a pharmacokinetic analysis conducted on actual patients with PD showing that MP significantly prolongs the ON time. The advantages of MP as a treatment for PD have been confirmed: it is inexpensive, as effective as LD, works faster and longer than LD, and does not increase dyskinesia.

Can We Differentiate Between Organic and Functional Bladder Outlet Obstruction in Males With Parkinson's Disease?

To determine the type of bladder outlet obstruction (BOO) in patients with Parkinson's disease (PD). A case-control study was carried out in 46 patients divided into two groups. Group 1 formed by 23 PD patients with BOO (a URA parameter ≥ 29 cm H2O). Group 2 formed by 23 patients with benign prostatic hyperplasia (BPH) and compressive obstruction (an opening pressure > 35 cm H2O) and URA parameter ≥ 29 cm H2O). Both groups underwent a pressure-flow study to calculate Dynamic Urethral Resistance Relationship (DURR) patterns. Based on previous research, we describe two types of DURR pattern. Pattern A typical of dynamic or functional obstruction and pattern B typical of static or organic obstruction. We found that PD patients had a significantly higher frequency of pattern A (70%) than BPH patients (4%). Other significant differences between groups were age (greater in PD group), bladder compliance (greater in PD group), maximum flow rate [Qmax (greater in BPH group)], maximum detrusor pressure [Pmax (greater in BPH group)], detrusor pressure at maximum flow rate [PQmax (greater in BPH group)], opening detrusor pressure (greater in BPH group), and the bladder contractility parameters BCI and Wmax (greater in BPH group). There were no significant differences in perineal voiding electromyography (EMG) activity between groups nor relationship between voiding EMG activity and the type of DURR pattern. Our results are consistent with the usefulness of the DURR pattern to differentiate between functional and organic BOO in PD patients. Most PD patients have functional obstruction although a minority has organic obstruction consistent with BPH.

Foot-Floor Contact Sequences: A Metric for Gait Assessment in Parkinson's Disease after Deep Brain Stimulation.

Digital gait monitoring is increasingly used to assess locomotion and fall risk. The aim of this work is to analyze the changes in the foot-floor contact sequences of Parkinson's Disease (PD) patients in the year following the implantation of Deep Brain Stimulation (DBS). During their best-ON condition, 30 PD patients underwent gait analysis at baseline (T0), at 3 months after subthalamic nucleus DBS neurosurgery (T1), and at 12 months (T2) after subthalamic nucleus DBS neurosurgery. Thirty age-matched controls underwent gait analysis once. Each subject was equipped with bilateral foot-switches and a 5 min walk was recorded, including both straight-line and turnings. The walking speed, turning time, stride time variability, percentage of atypical gait cycles, stance, swing, and double support duration were estimated. Overall, the gait performance of PD patients improved after DBS, as also confirmed by the decrease in their UPDRS-III scores from 19.4 ± 1.8 to 10.2 ± 1.0 (T0 vs. T2) (p < 0.001). In straight-line walking, the percentages of atypical cycles of PD on the more affected side were 11.1 ± 1.5% (at T0), 3.1 ± 1.5% (at T1), and 5.1 ± 2.4% (at T2), while in controls it was 3.1 ± 1.3% (p < 0.0005). In turnings, this percentage was 13.7 ± 1.1% (at T0), 7.8 ± 1.1% (at T1), and 10.9 ± 1.8% (at T2), while in controls it was 8.1 ± 1.0% (p < 0.001). Therefore, in straight-line walking, the atypical cycles decreased by 72% at T1, and by 54% at T2 (with respect to baseline), while, in turnings, atypical cycles decreased by 43% at T1, and by 20% at T2. The percentage of atypical gait cycles proved an informative digital biomarker for quantifying PD gait changes after DBS, both in straight-line paths and turnings.

Kinematic-Muscular Synergies Describe Human Locomotion with a Set of Functional Synergies.

Kinematics, kinetics and biomechanics of human gait are widely investigated fields of research. The biomechanics of locomotion have been described as characterizing muscle activations and synergistic control, i.e., spatial and temporal patterns of coordinated muscle groups and joints. Both kinematic synergies and muscle synergies have been extracted from locomotion data, showing that in healthy people four-five synergies underlie human locomotion; such synergies are, in general, robust across subjects and might be altered by pathological gait, depending on the severity of the impairment. In this work, for the first time, we apply the mixed matrix factorization algorithm to the locomotion data of 15 healthy participants to extract hybrid kinematic-muscle synergies and show that they allow us to directly link task space variables (i.e., kinematics) to the neural structure of muscle synergies. We show that kinematic-muscle synergies can describe the biomechanics of motion to a better extent than muscle synergies or kinematic synergies alone. Moreover, this study shows that at a functional level, modular control of the lower limb during locomotion is based on an increased number of functional synergies with respect to standard muscle synergies and accounts for different biomechanical roles that each synergy may have within the movement. Kinematic-muscular synergies may have impact in future work for a deeper understanding of modular control and neuro-motor recovery in the medical and rehabilitation fields, as they associate neural and task space variables in the same factorization. Applications include the evaluation of post-stroke, Parkinson's disease and cerebral palsy patients, and for the design and development of robotic devices and exoskeletons during walking.

SMALL FIBER NEUROPATHY DIAGNOSIS IN PARKINSON'S DISEASE PATIENTS: A CASE SERIES

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Motor impairments, particularly in gait and balance, significantly reduce the quality of life in patients, increasing the risk of falls. Non-motor symptoms, including autonomic dysfunctions and peripheral neuropathy, are prevalent as the disease progresses. Peripheral neuropathy, present in 55% of PD patients, manifests with sensory loss, postural instability, and pain, further impairing motor function and increasing fall risk. This study aimed to adapt and test a simple method to identify small fiber neuropathy in PD patients, specifically using the Skin Wrinkling Test (SWT), and to correlate its findings with autonomic dysfunctions. Four PD patients were evaluated using questionnaires (Non-Motor Symptoms Questionnaire, COMPASS-31) and SWT. All patients showed alterations in the SWT, suggesting the presence of small fiber neuropathy, regardless of disease duration or comorbid conditions such as diabetes. Despite the small sample size, our findings support the SWT as a practical tool for assessing small fiber neuropathy in clinical practice. Further large-scale studies are needed to validate these results and their implications for diagnosing peripheral neuropathy in PD patients.

PET Imaging with [18F]ROStrace Detects Oxidative Stress and Predicts Parkinson's Disease Progression in Mice.

Although the precise molecular mechanisms responsible for neuronal death and motor dysfunction in late-onset Parkinson's disease (PD) are unknown, evidence suggests that mitochondrial dysfunction and neuroinflammation occur early, leading to a collective increase in reactive oxygen species (ROS) production and oxidative stress. However, the lack of methods for tracking oxidative stress in the living brain has precluded its use as a potential biomarker. The goal of the current study is to address this need through the evaluation of the first superoxide (O2•-)-sensitive radioactive tracer, [18F]ROStrace, in a model of late-onset PD. To achieve this goal, MitoPark mice with a dopaminergic (DA) neuron-specific deletion of transcription factor A mitochondrial (Tfam) were imaged with [18F]ROStrace from the prodromal phase to the end-stage of PD-like disease. Our data demonstrate [18F]ROStrace was sensitive to increased oxidative stress during the early stages of PD-like pathology in MitoPark mice, which persisted throughout the disease course. Similarly to PD patients, MitoPark males had the most severe parkinsonian symptoms and metabolic impairment. [18F]ROStrace retention was also highest in MitoPark males, suggesting oxidative stress as a potential mechanism underlying the male sex bias of PD. Furthermore, [18F]ROStrace may provide a method to identify patients at risk of Parkinson's before irreparable neurodegeneration occurs and enhance clinical trial design by identifying patients most likely to benefit from antioxidant therapies.

Genetically stratified Parkinson's disease with freezing of gait is related to specific pattern of cognitive impairment and non-motor dominant endophenotype.

Freezing of gait (FOG) is an important milestone in the individual disease trajectory of people with Parkinson's disease (PD). Based on the cognitive model of FOG etiology, the mechanism behind FOG implies higher executive dysfunction in PDFOG+. To test this model, we investigated the FOG-related phenotype and cognitive subdomains in idiopathic PD (iPD) patients without genetic variants linked to PD from the Luxembourg Parkinson's study. A cross-sectional analysis comparing iPDFOG+ (n = 118) and iPDFOG- (n = 378) individuals was performed, followed by the application of logistic regression models. Consequently, regression models were fitted for a subset of iPDFOG+ (n = 35) vs. iPDFOG- (n = 126), utilizing a detailed neuropsychological battery to assess the association between FOG and cognitive subdomains. Both regression models were adjusted for sociodemographic confounders and disease severity. iPDFOG+ individuals presented with more motor complications (MDS-UPDRS IV) compared to iPDFOG- individuals. Moreover, iPDFOG+ individuals exhibited a higher non-motor burden, including a higher frequency of hallucinations, higher MDS-UPDRS I scores, and more pronounced autonomic dysfunction as measured by the SCOPA-AUT. In addition, iPDFOG+ individuals showed lower sleep quality along with lower quality of life (measured by PDSS and PDQ-39, respectively). The cognitive subdomain analysis in iPDFOG+ vs. iPDFOG- indicated lower scores in Benton's Judgment of Line Orientation test and CERAD word recognition, reflecting higher impairment in visuospatial, executive function, and memory encoding. We determined a significant association between FOG and a clinical endophenotype of PD with higher non-motor burden. While our results supported the cognitive model of FOG, our findings point to a more widespread cortical impairment across cognitive subdomains beyond the executive domain in PDFOG+ with additional higher impairment in visuospatial function and memory encoding.

Machine learning model base on metabolomics and proteomics to predict cognitive impairment in Parkinson’s disease

There is an urgent need to identify predictive biomarkers of Parkinson’s disease (PD) with cognitive impairment (PDCI) in order to individualize patient management, ensure timely intervention, and improve prognosis. The aim of this study was to screen for these biomarkers by comparing the plasma proteome and metabolome of PD patients with or without cognitive impairment. Proteomics and metabolomics analyses were performed on a discover cohort. A machine learning model was used to identify candidate protein and metabolite biomarkers of PDCI, which were validated in an independent cohort. The predictive ability of these biomarkers for PDCI was evaluated by plotting receiver operating characteristic curves and calculating the area under the curve (AUC). Moreover, we assessed the predictive ability of these proteins in combination with neuroimaging. In the discover cohort (n = 100), we identified 25 protein features with best results in the machine learning model, including top-ranked PSAP and H3C15. The two-proteins were used for model construction, achieving an Area under the curve (AUC) of 0.951 in the train set and AUC of 0.981 in the test set. Similarly, the model gives a rank list of endogenous metabolite features, Glycocholic Acid and 6-Methylnicotinamide were two top features. Combining these two markers further got the AUC of 0.969 in train set and 0.867 in the test set. To validate the performance of the protein biomarkers, we performed targeted analysis of selected proteins (H3C15 and PSAP) and proteins likely associated with PDCI (NCAM2 and LAMB2) using parallel reaction monitoring in validation cohort (n = 116). The AUC of the classifier built with H3C15 and PSAP is 0.813. Moreover, when combining H3C15, PSAP, NCAM2, and LAMB2, the model achieved AUC of 0.983 in the train set, AUC of 0.981 in the test set, and AUC of 0.839 in the validation set. Furthermore, we verified that these protein markers we discovered can improve the predictive effect of neuroimaging on PDCI: the classifier built with neuroimaging features had AUC of 0.833, which improved to 0.905 when combined with H3C15. Taken together, our integrated proteomics and metabolomics analysis successfully identified potential biomarkers for PDCI. Additionally, H3C15 showed promise in enhancing the predictive performance of neuroimaging for cognitive impairment.

Natural variation in age-related dopamine neuron degeneration is glutathione dependent and linked to life span

Aging is the biggest risk factor for Parkinson's disease (PD), suggesting that age-related changes in the brain promote dopamine neuron vulnerability. It is unclear, however, whether aging alone is sufficient to cause significant dopamine neuron loss, and if so, how this intersects with PD-related neurodegeneration. Here, through examining a large collection of naturally varying Drosophila strains, we find a strong relationship between life span and age-related dopamine neuron loss. Strains with naturally short-lived animals exhibit a loss of dopamine neurons without generalized neurodegeneration, while animals from long-lived strains retain dopamine neurons across age. Metabolomic profiling reveals lower glutathione levels in short-lived strains which is associated with elevated levels of reactive oxygen species (ROS), sensitivity to oxidative stress, and vulnerability to silencing the familial PD gene parkin. Strikingly, boosting neuronal glutathione levels via glutamate-cysteine ligase (Gcl) overexpression is sufficient to normalize ROS levels, extend life span, and block dopamine neurons loss in short-lived backgrounds, demonstrating that glutathione deficiencies are central to neurodegenerative phenotypes associated with short longevity. These findings may be relevant to human PD pathogenesis, where glutathione depletion is reported to occur in the idiopathic PD patient brain through unknown mechanisms. Building on this, we find reduced expression of the Gcl catalytic subunit in both Drosophila strains vulnerable to age-related dopamine neuron loss and in the human brain from familial PD patients harboring the common LRRK2 G2019S mutation. Our study across Drosophila and human PD systems suggests that glutathione synthesis and levels play a conserved role in regulating age-related dopamine neuron health.

AIMP2 accumulation in brain leads to cognitive deficits and blood secretion in Parkinson’s disease

BackgroundPropagation of neuronal α-synuclein aggregate pathology to the cortex and hippocampus correlates with cognitive impairment in Parkinson’s disease (PD) dementia and dementia with Lewy body disease. Previously, we showed accumulation of the parkin substrate aminoacyl-tRNA synthetase interacting multifunctional protein-2 (AIMP2) in the temporal lobe of postmortem brains of patients with advanced PD. However, the potential pathological role of AIMP2 accumulation in the cognitive dysfunction of patients with PD remains unknown.MethodsWe performed immunofluorescence imaging to examine cellular distribution and accumulation of AIMP2 in brains of conditional AIMP2 transgenic mice and postmortem PD patients. The pathological role of AIMP2 was investigated in the AIMP2 transgenic mice by assessing Nissl-stained neuron counting in the hippocampal area and Barnes maze to determine cognitive functions. Potential secretion and cellular uptake of AIMP2 was monitored by dot blot analysis and immunofluorescence. The utility of AIMP2 as a new PD biomarker was evaluated by dot blot and ELISA measurement of plasma AIMP2 collected from PD patients and healthy control followed by ROC curve analysis.ResultsWe demonstrated that AIMP2 is toxic to the dentate gyrus neurons of the hippocampus and that conditional AIMP2 transgenic mice develop progressive cognitive impairment. Moreover, we found that neuronal AIMP2 expression levels correlated with the brain endothelial expression of AIMP2 in both AIMP2 transgenic mice and in the postmortem brains of patients with PD. AIMP2, when accumulated, was released from the neuronal cell line SH-SY5Y cells. Secreted AIMP2 was taken up by human umbilical vein endothelial cells. Consistent with the fact that AIMP2 can be released into the extracellular space, we showed that AIMP2 transgenic mice have higher levels of plasma AIMP2. Finally, ELISA-based assessment of AIMP2 in plasma samples from patients with PD and controls, and subsequent ROC curve analysis proved that high plasma AIMP2 expression could serve as a reliable molecular biomarker for PD diagnosis.ConclusionsThe pathological role in the hippocampus and the cell-to-cell transmissibility of AIMP2 provide new therapeutic avenues for PD treatment, and plasma AIMP2 combined with α-synuclein may improve the accuracy of PD diagnosis in the early stages.

ER-mitochondria distance is a critical parameter for efficient mitochondrial Ca2+ uptake and oxidative metabolism

IP3 receptor (IP3R)-mediated Ca2+ transfer at the mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) drives mitochondrial Ca2+ uptake and oxidative metabolism and is linked to different pathologies, including Parkinson’s disease (PD). The dependence of Ca2+ transfer efficiency on the ER-mitochondria distance remains unexplored. Employing molecular rulers that stabilize ER-mitochondrial distances at 5 nm resolution, and using genetically encoded Ca2+ indicators targeting the ER lumen and the sub-mitochondrial compartments, we now show that a distance of ~20 nm is optimal for Ca2+ transfer and mitochondrial oxidative metabolism due to enrichment of IP3R at MERCS. In human iPSC-derived astrocytes from PD patients, 20 nm MERCS were specifically reduced, which correlated with a reduction of mitochondrial Ca2+ uptake. Stabilization of the ER-mitochondrial interaction at 20 nm, but not at 10 nm, fully rescued mitochondrial Ca2+ uptake in PD astrocytes. Our work determines with precision the optimal distance for Ca2+ flux between ER and mitochondria and suggests a new paradigm for fine control over mitochondrial function.

Generation of an induced pluripotent stem cell line (HMSCATi004-A) from an early onset Parkinson’s disease patient with PRKN gene mutation

Parkin (PRKN) is recognized as causative gene in early-onset Parkinson’s disease (PD). Induced pluripotent stem cells (iPSCs) were derived from a 29-year-old PD patient carrying a heterozygous c.823C > T (p.R275W) variant and an exon 2–4 deletion in PRKN. The Generated iPSCs maintain a normal karyotype, express pluripotency markers, and retain the ability to differentiate into the three germ layers. This iPSC line serves as a valuable cellular model for investigating the pathogenesis of early-onset PD and development of potential therapeutic interventions.

Gait analysis in the early stage of Parkinson's disease with a machine learning approach.

Gait disorder is a prominent motor symptom in Parkinson's disease (PD), objective and quantitative assessment of gait is essential for diagnosing and treating PD, particularly in its early stage. This study utilized a non-contact gait assessment system to investigate gait characteristics between individuals with PD and healthy controls, with a focus on early-stage PD. Additionally, we trained two machine learning models to differentiate early-stage PD patients from controls and to predict MDS-UPDRS III score. Early-stage PD patients demonstrated reduced stride length, decreased gait speed, slower stride and swing speeds, extended turning time, and reduced cadence compared to controls. Our model, after an integrated analysis of gait parameters, accurately identified early-stage PD patients. Moreover, the model indicated that gait parameters could predict the MDS-UPDRS III score using a machine learning regression approach. The non-contact gait assessment system facilitates the objective and quantitative evaluation of gait disorder in PD patients, effectively distinguishing those in the early stage from healthy individuals. The system holds significant potential for the early detection of PD. It also harnesses gait parameters for a reasoned prediction of the MDS-UPDRS III score, thereby quantifying disease severity. Overall, gait assessment is a valuable method for the early identification and ongoing monitoring of PD.

Association between the Val66Met (rs6265) polymorphism of the brain-derived neurotrophic factor (BDNF) gene, BDNF protein level in the blood and the risk of developing early‑onset Parkinson's disease.

Brain-derived neurotrophic factor (BDNF) is involved in the maintenance of dopamine level and the survival of dopaminergic neurons, which may affect the functionality of brain structures responsible for motor and cognitive function. The aim of the study was to assess the association of individual and combined single nucleotide polymorphism (SNP) in the rs6265 BDNF (Val66Met), rs397595 DAT (SLC6A3), and rs4680 COMT (Val158Met) genes with early‑onset of Parkinson's disease (PD) patients. Moreover, we assessed the association between the BDNF Val66Met polymorphism and the level of BDNF protein in the serum of patients with PD and controls. The study involved 163 patients with idiopathic PD divided into early onset (<55 years) and late‑onset (>55 years) groups and 91 healthy age‑matched people (Control). The SNP were determined using the TaqMan Real‑Time PCR method. Serum BDNF levels were determined by ELISA assay. The risk of developing early PD in people with the BDNF genotype AG increases threefold in comparison with the carriers of the BDNF genotype GG. In PD patients and healthy people with the BDNF genotypes AG and AA, a lower serum BDNF level was found compared to those with the BDNF genotype GG in both groups. The results of our study indicate that the presence of the Val66Met BDNF gene polymorphism is associated with reduced blood BDNF levels and an elevated risk of developing early‑onset PD. This effect appears to be more pronounced in men.

Skin adhesion of a newly developed, bioequivalent rotigotine patch formulation in comparison to the originator product: Results of a multi-center, randomized, crossover trial in patients with Parkinson's disease.

To demonstrate adequate skin adhesion of a new once-daily rotigotine transdermal patch (ROT-TDS) compared to the originator product (reference) in patients with Parkinson's disease (PD). Pharmacokinetic bioequivalence (PK BE) was assessed with the 4 mg/24h patches in healthy adults in a single-/multiple-dose, crossover trial. The trial investigating skin adhesion in PD patients (stable dose ≥ 8 mg/day rotigotine) was performed with the 8 mg/24h patches as a multiple-dose, crossover trial (4 alternating once-daily patch applications). Skin status (seborrhea, sweating) was characterized at screening. Adhesion was assessed 5 minutes after application and 5 minutes before removal of each patch. Systemic safety and skin irritation/sensitization were monitored. ROT-TDS was bioequivalent to the reference product in the PK BE trial in 48 randomized healthy subjects. In the skin adhesion trial in 43 randomized PD patients, the cumulative mean percentage of adhesion (90% CI) at the end-of-dosing interval was 92.948% (90.156 - 95.740%) for ROT-TDS and 90.471% (87.574 - 93.367%) for the reference. For ROT-TDS, 80.23% of patches were ≥ 90% adhered at the end-of-dosing interval, while this was the case for 67.44% of the reference patches. Safety and skin tolerability of both products were comparable; the most frequent treatment-related adverse event was application-site pruritus for both treatments at comparable extent. ROT-TDS - with shown BE to the originator reference product - displayed similar safety and local tolerability as the reference product in patients with PD. The results show a trend to improved skin adhesion of the new patch compared to the reference in the target population.

Diagnostic and therapeutic challenges in PD-associated non-motor symptoms: the roles of neurologists and consultant physicians.

In addition to their motor symptoms, almost all Parkinson's disease patients report non-motor symptoms (NMS) and, in the later course of the disease, non-motor fluctuations as well. These NMS encompass e.g. neuropsychiatric, gastrointestinal, urogenital, cardiovascular symptoms and pain. For a long time, these symptoms received no or at best very little attention, but there is a growing trend towards their recognition and treatment. Despite this progress, significant gaps remain, particularly due to the sometimes-limited expertise among neurologists regarding these symptoms. The clinical need to consequently treat these NMS raises the question of whether Movement Disorder specialists should and can address them sufficiently or if additional consultant physicians have to be enrolled. Therefore, our objective is to establish benchmarking criteria to outline a potential way forward. Ideally, Movement Disorder specialists should take on greater responsibility when treating non-motor PD symptoms, integrating diagnostic and therapeutic pathways from other medical disciplines where feasible.

Evaluating a motor progression connectivity model across Parkinson's disease stages.

Stimulation of a specific site in the dorsolateral subthalamic nucleus (STN) was recently associated with slower motor progression in Parkinson's Disease (PD), based on the deep brain stimulation (DBS) in early-stage PD pilot clinicaltrial. Here, subject-level visualizations are presented of this early-stage PD dataset to further describe the relationship between active contacts and motor progression. This study also evaluates whether stimulation of the sweet spot and connectivity model associated with slower motor progression is alsoassociated with improvements in long-term motor outcomes in patients with advanced-stage PD. Active contacts of the early-stage PD cohort (N = 14) were analyzed alongside the degree of two-year motor progression. Sweet spot and connectivity models derived from the early-stage PD cohort were then used to determine how well they can estimate the variance inlong-term motor outcomes in an independent STN-DBS cohort of advanced-stage PD patients (N = 29). In early-stage PD, proximity of stimulation to the dorsolateral STN wasassociated with slower motor progression. In advanced-stage PD, stimulation proximity to the early PD connectivity model and sweet spot were associated with better long-term motor outcomes (R = 0.60, P < 0.001; R = 0.37, P = 0.046, respectively). Results suggest stimulation of a specific site in the dorsolateral STN isassociated with both slower motor progression and long-term motor improvements in PD.