Parkinsonism & Related Disorders

BackgroundCyclin-dependent kinase 5 (CDK5) is a multifunctional enzyme involved in neuronal development, maturation and survival. CDK5 activity is tightly regulated by association with regulatory proteins p35 and p39. Upon neuronal insults, increased intracellular calcium activates calpain, cleaving p35 into p25, which has a higher affinity for CDK5. p25 hyperactivates CDK5, initiating apoptotic cascades that lead to significant dopaminergic (DAergic) loss that can leads to neurodegenerative disorders, such as Parkinsons disease (PD). ObjectiveThis study investigates hyperactivation of CDK5/p25 in the 6-hydroxydopamine (6-OHDA) rat model of PD and specific inhibition of CDK5/p25 by truncated peptide 5 (TP5). TP5 was investigated for amelioration of 6-OHDA induced behaviour impairments and significant protection of dopamine neurons through tyrosine hydroxylase (TH). Methods6-OHDA induced motor impairments and reduced TH. Motor assessments included locomotor activity, beam transversal, fixed speed rotarod and amphetamine-induced rotations. Immunohistochemistry investigated DAergic neurodegeneration using TH levels and immunoprecipitation and assay investigated CDK5 activity. ResultsPre-administration of TP5 maintained locomotor activity, preserved beam transversal scores, protected motor coordination and attenuated amphetamine induced rotations in 6-OHDA lesioned rats, all indicative of neuroprotection by TP5. 6-OHDA without pretreatment of TP increased CDK5 activation. CDK5 activity in TP5+6-OHDA animals was not significantly different from artificial cerebrospinal fluid (aCSF) treated sham surgery controls. Immunohistochemistry revealed significant TH protection within the substantia nigra (SN) of TP5 pretreated animals. Conclusions6-OHDA increases CDK5 activity. Hyperactive CDK5/p25 inhibition in the 6-OHDA model has neuroprotective capability, protecting against the development of a toxin-based induction of PD-like motor phenotypes and pathology. This supports CDK5/p25 specific inhibition as a target for further neuroprotective therapeutic development.

BackgroundAmong motor symptoms of Parkinsons disease (PD), including rigidity and resting tremor, bradykinesia is a mandatory feature to define the parkinsonian syndrome. MDS-UPDRS III is the worldwide reference scale to evaluate the parkinsonian motor impairment, especially bradykinesia. However, MDS-UPDRS III constitutes an agent-based score making reproducible measurements and follow-up challenging. ObjectivesUsing a deep learning approach, we developed a tool to compute an objective score of bradykinesia based on the gold-standard MDS-UPDRS III. MethodsIn the Movement Disorder unit of Avicenne University Hospital, we acquired a large database of videos of parkinsonian patients performing MDS-UPDRS III protocols. We applied two deep learning algorithms to detect a two-dimensional (2D) skeleton of the hand composed of 21 predefined points, and transposed it into a three-dimensional (3D) skeleton. ResultsWe developed a 2D and 3D automated analysis tool to study the evolution of several key parameters during the protocol repetitions of the MDS-UPDRS III. Scores from 2D automated analysis showed a significant correlation with gold-standard ratings of MDS-UPDRS III, measured with coefficients of determination for the tapping (0.609) and hand movements (0.701) protocols using decision tree algorithms. The individual correlations of the different parameters measured with MDS-UPDRS III scores carry meaningful information and are consistent with MDS-UPDRS III guidelines. ConclusionWe developed a deep learning-based tool to reliably score and analyze bradykinesia for parkinsonian patients.

BackgroundParkinsons Disease (PD) patients with postural instability and gait disorder (PIGD) subtype are at increased risk for falls compared to the tremor-dominant subtype. We aimed to establish an easy clinical balance tool to rapidly and reliably identify PIGD patients, potentially important for directing healthcare resources or research phenotyping. Methods45 consecutive patients with PD completed clinical testing including Romberg, tandem stance, single leg stance, 360{degrees} turning and 10-meter walking. MDS-UPDRS part II and III, collected as part of regular follow-up, was used to classify disease subtype. Multinominal logistic regression models were fitted to find optimal subtype predictors and compared using receiver operating characteristic (ROC) curves. ResultsUnassisted tandem stand duration and time to turn 360{degrees} were significantly different between PIGD and tremor dominant subtypes. Both tandem standing and 360{degrees} turning showed very high predictive accuracy to predict PD subtype with an area under the ROC curve (AUC) of 86.6% and 88% respectively, which increased to 91.4% by combining both measures. Optimal cut-off values for identifying PD subtypes were tandem standing less than 20s and 360{degrees} turning longer than 6.5s. ConclusionTandem stand duration and 360{degrees} turning are easy to apply clinical tests that rapidly identify PD patients with PIGD subtype with high sensitivity and specificity. These findings may be useful in the clinic to identify PD patients current falls risk or screening for research studies. Plain Language SummaryBalance problems and falls are common in late-stage Parkinsons Disease, affecting nearly 70% of patients 10 years post-diagnosis. In contrast, Parkinsons patients who complain mainly of shaking (tremor) are less liable to fall. We set out to find an easy and reliable bedside test to distinguish patients at risk of falls with early Parkinsons. This is important so that resources can be targeted to patients in need of support such as physiotherapy and fall prevention. 45 patients with Parkinsons disease participated in this study and completed a battery of balance tests completed within the time of their regular follow-up appointment. We found that tandem standing duration - a test where patient stand still in the heel-to-toe position - and time taken to complete a full circle, were highly reliable in detecting patients with balance and gait problems. Specifically, patients with balance and gait problems were unable to tandem stand for more than 20 seconds and took more than 6.5 seconds to turn a full circle. Together, these two tests that take a minute to complete in the clinic, and may help improve the care for patients with Parkinsons as a quick screening tool to identify Parkinsons disease at risk of falls.

BackgroundThe availability of deep brain stimulation (DBS), a highly efficacious treatment for several movement disorders, remains low in developing countries, with scarce data available on utilization and outcomes. ObjectivesWe characterized the DBS cohort and outcomes at a Malaysian quaternary medical centre. MethodsA retrospective chart review was done on DBS-related surgery at the University of Malaya, including clinico-demographic, genetics, and outcomes data focusing on post-operative medication reduction and complications. Results149 Parkinsons disease (PD) patients underwent DBS targeting the subthalamic nucleus. Six had globus pallidus internus DBS (primarily for dystonia). Only 16.1% of cases were government-funded. Of the 133 PD patients operated in the past decade (2013-2022), 25 (18.8%) had disease duration <5 years. At 6-12 months post-DBS, median levodopa-equivalent daily dosage (LEDD) reduction was 440.5 [418.9] mg/day, corresponding to a reduction of [&ge;]50% and [&ge;]30% in 42.2% and 69.8% of patients, respectively. LEDD reductions were larger in the early-onset and short-duration subgroups. Three patients (1.9% of 155) had symptomatic intracranial hemorrhage, resulting in stroke in two. Pathogenic monogenic or GBA1 variants were detected in 12/61 (19.7%) of patients tested, mostly comprising the "severe" GBA1 variant p.L483P (14.8%). ConclusionThis is the largest report on DBS from Southeast Asia. The procedures were effective, and complication rates on par with international norms. Our study found a high frequency of GBA1-PD; and included a substantial number of patients with short-duration PD, who had good outcomes. It also highlights the inequity of access to device-aided therapy.

BackgroundAlthough levodopa remains the gold standard treatment for Parkinsons disease (PD), its chronic use is associated with levodopa-induced dyskinesia (LID), a motor complication that impacts prognosis, quality of life, and treatment costs. Most known LID-associated factors have been identified in European-descendant populations. ObjectivesTo describe the epidemiology of LID in Latin American and Caribbean (LATAM) countries and assess the relevance of known and novel LID-associated factors in this population. MethodsWe conducted a cross-sectional study using data from the Latin American Research consortium on the Genetics of Parkinsons Disease (LARGE-PD). We included PD patients with information on LID status and levodopa use from eight LATAM countries. LID prevalence was calculated overall and by country. Countries were compared on demographic and clinical variables. Logistic regression was used to identify associations with LID. ResultsA total of 3,695 PD patients (58.8% male) were included. Overall LID prevalence was 25.4% [95% CI: 24.06-26.87], ranging from 9.3% in Colombia to 45.1% in Puerto Rico. Prevalence increased progressively with longer disease duration. Country comparisons showed that not all known LID-associated factors explained prevalence differences. In logistic regression, fast disease progression was significantly associated with LID (OR: 1.55, 95%CI: 1.16-2.07), while sex was not (OR: 1.02, 95%CI: 0.87-1.18). ConclusionsThis is the largest study on LID epidemiology in LATAM. While some known risk factors remain relevant, others, like sex, do not, underscoring the need for population-specific studies. Future work should integrate environmental, clinical, and genetic data to better understand LID mechanisms.

PurposeDespite advances in recent years, genetic testing for Parkinsons disease (PD) is still underutilized in clinical practice. A 2019 questionnaire of movement disorder specialists found low rates of genetic testing in PD and barriers such as cost and insurance coverage. Since that time, PD GENEration as well as several international programs have broadly increased access to genetic testing and counseling for people with PD. A new survey sent out in 2024 examined how genetic testing for PD has changed over the past 5 years. MethodsBetween October 2024-January 2025, 621 movement disorders specialists from the Parkinsons Study Group (PSG) were invited by email to complete a questionnaire assessing knowledge, attitudes, and barriers to genetic testing in PD based on the 2019 survey. Results119 total PSG clinicians from the United States and Canada responded to the questionnaire. When compared to results from 2019, 2024 survey respondents reported increased comfort and willingness to order genetic testing, including reduced fears of negative repercussions. PD GENEration-affiliated sites reported significantly higher genetic testing volume and patients with known genetic variants. Conclusions2024 survey respondents report greater comfort with genetic testing in PD compared to 2019, concurrent with the launch of PD GENEration.

ObjectiveAlthough Levodopa-carbidopa intestinal gel (LCIG) treatment has shown to be efficacious in motor and some non-motor symptoms (NMS), not all the patients with advanced Parkinsons disease (PD) are ideal candidates. To improve their selection analysis knowledge of prognostic factors is of great importance. We aimed to develop a novel machine learning model to predict the clinical outcomes of patients with advanced PD at 2 years under the LCIG therapy. MethodsThis was a longitudinal 24-month, observational study of 59 patients with advanced PD of a Greek multicenter registry under LCIG treatment from September 2019 to September 2021. Motor status was assessed with the Unified Parkinsons Disease Rating Scale (UPDRS) part III (off) and IV. NMS were assessed by the NMS Questionnaire (NMSQ) and the Geriatric Depression Scale (GDS), the quality of life by PDQ-39 and severity by Hoehn &Yahr (HY). Multivariate linear regression, ARIMA, SARIMA, and Long Short-Term Memory-recurrent neural network (LSTM-RNN) models were used. ResultsDyskinesia duration and quality of life were significantly improved with LCIG (19% and 10% greater improvement for men than women, respectively). Multivariate linear regression models showed that UPDRS-III was decreased by 1.5 and 4.39 units per one unit of increase of the PDQ-39, UPDRS-IV indexes, respectively. Among all the time series models, the LSTM-RNN model predicts these clinical characteristics with highest accuracy (mean square error =0.0069) ConclusionsThe LSTM-RNN model predicts with highest accuracy sex dependent clinical outcomes of patients with advanced PD after two years of LCIG therapy.

22q11.2 microdeletion syndrome (22qDS) was recently identified as a risk factor for development of early-onset Parkinsons disease (PD). The classical motor manifestations of this disease are preceded by early signs and symptoms of neurodegeneration. The progression of 22qDS-associated PD is unknown. We aimed to evaluate the presence of prodromal PD in a group of adults with 22qDS using the Movement Disorders Society (MDS) Criteria for Prodromal PD. Thirty-eight persons with 22qDS and 13 age-matched controls participated in the study, and their results were compared using the Mann-Whitney U test. Persons with 22qDS had lower scores on olfaction testing (p=7.42Ex10-5), higher scores on the COMPASS 31 scale for dysautonomia (p=2.28x10-3) and on the motor evaluation using Movement Disorder Society (MDS)-sponsored revision of Unified Parkinsons Disease Rating Scale motor subscore (UPDRS-III) (p=1.84x10-4), compared with healthy controls. Home polysomnogram did not find participants with REM-sleep behavior disorder. Integrity of nigrostriatal dopaminergic system was evaluated by PET-CT imaging of presynaptic dopamine with 18F-PR04.MZ. Patients showed significantly higher specific binding ratios in the striatum, compared to controls (p=9.57x10-3 at the caudate nuclei). Two patients with 22qDS (5.2%) had decreased uptake in the posterior putamen (less than 60% of controls) and one fulfilled MDS criteria for prodromal PD. These results show that patients with 22qDS manifest some signs and symptoms of prodromal PD such as hyposmia, dysautonomia and mild movement alterations. In the majority, this was associated with elevated dopaminergic signaling, suggesting that loss of dopaminergic neurons may not be the cause. A smaller subgroup did show evidence of a decrease in nigrostriatal dopaminergic signaling, as seen in classical prodromal PD. Longitudinal studies are necessary to understand the progression to and risk of PD in persons with 22qDS.

BackgroundLevodopa-induced dyskinesia (LID) is a common motor complication of levodopa therapy in patients with Parkinsons disease (PD). Doxycycline is a widely used and inexpensive tetracycline with anti-inflammatory properties. ObjectiveEvaluate the efficacy and safety of doxycycline in patients with PD and LID. MethodsThis was an open-label, single-center, phase 2 proof-of-concept study in patients with PD with mild functional impact of dyskinesia, which used levodopa three times daily, in a movement disorders clinic in Brazil. Participants were treated with doxycycline 200 mg/day for 12 weeks, with evaluations in baseline, week 4, and week 12 of treatment. The primary outcome measure was the change from baseline in the Unified Dyskinesia Rating Scale (UDysRS) total score at week 12, evaluated by two blinded raters. Key secondary outcomes measures were OFF time and ON time with troublesome dyskinesia in the PD home diary. ResultsEight patients with PD were treated and evaluated. Doxycycline 200 mg/day reduced the UDysRS total score in week 12, compared with baseline (Friedmans X2 = 9.6, p = 0.008). Further, doxycycline reduced the ON time with troublesome dyskinesia (Friedmans X2 = 10.8, p = 0.004) without worsening parkinsonism. There were no severe adverse events, and dyspepsia was the commonest event. ConclusionsDoxycycline was effective in reducing LID and safe after a 12-week treatment. Further well-designed placebo-controlled clinical trials with a longer duration and a larger number of participants are needed.

ImportanceIf history teaches, as cardiac pacing moved from fixed-rate to on-demand delivery in in 80s of the last century, there are high probabilities that closed-loop and adaptive approaches will become, in the next decade, the natural evolution of conventional Deep Brain Stimulation (cDBS). However, while devices for aDBS are already available for clinical use, few data on their clinical application and technological limitations are available so far. In such scenario, gathering the opinion and expertise of leading investigators worldwide would boost and guide practice and research, thus grounding the clinical development of aDBS. ObservationsWe identified clinical and academically experienced DBS clinicians (n=21) to discuss the challenges related to aDBS. A 5-point Likert scale questionnaire along with a Delphi method was employed. 42 questions were submitted to the panel, half of them being related to technical aspects while the other half to clinical aspects of aDBS. Experts agreed that aDBS will become clinical practice in 10 years. In the present scenario, although the panel agreed that aDBS applications require skilled clinicians and that algorithms need to be further optimized to manage complex PD symptoms, consensus was reached on aDBS safety and its ability to provide a faster and more stable treatment response than cDBS, also for tremor-dominant Parkinsons disease patients and for those with motor fluctuations and dyskinesias. Conclusions and RelevanceDespite the need of further research, the panel concluded that aDBS is safe, promises to be maximally effective in PD patients with motor fluctuation and dyskinesias and therefore will enter into the clinical practice in the next years, with further research focused on algorithms and markers for complex symptoms.

BackgroundEffective, measurable, and non-invasive treatments for motor symptoms, gait and balance difficulties, and associated non-motor burden in Parkinsons disease (PD) remain limited. We aimed to assess the usability, safety/tolerability, and clinical efficacy of CUE1+, a wearable cueing and vibrotactile stimulation non-invasive device, in people with PD. MethodsThis 12-week, double-blind, randomised controlled trial was conducted at two UK sites in adults with idiopathic PD. Participants were randomly assigned (1:1) to receive either an active CUE1+ device or a sham device, worn on the sternum for 8 hours daily. Participants, investigators, and assessors were blinded to treatment allocation. The primary outcomes were usability and safety/tolerability of CUE1+. Secondary outcomes, including Movement Disorder Society-sponsored revision of the Unified PD Rating Scale (MDS-UPDRS) Part III, were assessed in the ON-medication state at baseline and week 13. FindingsFifty participants were randomised to sham stimulation (Group A; n=25) or active CUE1+ stimulation (Group B; n=25). Median age was 70.0 years (IQR 65.0-75.5) in Group A and 68.0 years (62.0-75.0) in Group B. Group A included 14 (56%) men; Group B, 13 (52%) men. Four participants (8.0%) discontinued: three (6.3%) from Group A, one (2.0%) from Group B. Compliance to allocated intervention was equally excellent in both groups. Mild, transient skin irritation occurred in two participants (4.2%). MDS-UPDRS Part III scores improved by -4.5 points (95%CI: -8.7, -0.4; p=0.043), in Group A and -15.6 points (95%CI: - 20.3, -10.9; p<0.0001) in Group B, with a between-group difference of 11.08 points (95%CI: 4.85-17.31; p=0.002). InterpretationCUE1+ is a safe and well-tolerated non-invasive device that improves motor and non-motor outcomes in PD. These findings suggest a potential therapeutic benefit and support further evaluation in large-scale RCTs and consideration for integration into health care pathways. FundingUKRI Knowledge Transfer Partnership, 2021-2022, round 4 and Charco Neurotech Ltd.

Background and PurposeNeuromodulation and physical therapy (PT) can both mitigate motor and non-motor symptoms of Parkinsons Disease (PD). There are a lack of studies examining the integration of transcutaneous auricular vagus nerve stimulation (taVNS) with PT or exercise for improving Parkinsonian symptoms. The study was designed to investigate the safety, tolerability, and feasibility of combining bilateral taVNS with PT to enhance the therapeutic benefits of exercise as medicine in a clinical setting. MethodsThis pilot study was a randomized, sham-controlled clinical trial. Participants were randomly assigned to receive active or sham bilateral taVNS in combination with physical therapy for 12 visits over 6 weeks. We quantified safety, tolerability, and feasibility outcomes, and explored changes in cardiovascular and motor function over time. ResultsWe observed taVNS was well tolerated without reported adverse events. We observed taVNS administered prior to physical therapy significantly decreased heart rate and blood pressure at rest. We observed the active taVNS treatment group exhibited more sustained improvements in motor function and balance compared to baseline. Due to the small size of the feasibility study, we did not detect between-group differences. Discussion and ConclusionsCombining taVNS with physical therapy was safe, feasible, and well-tolerated. Preliminary results suggest taVNS has the potential to enhance rehabilitation outcomes by modulating cardiovascular function prior to and during PT and exercise. These findings support the need for larger clinical trials and real-world studies investigating the integration of taVNS into PT and exercise methods for improving PD symptomology. Trial RegistrationClinicalTrials.gov NCT05871151

Background and Objectives: PD is the second most common neurodegenerative disorder and the fastest growing. Genetic factors account for [~]15% of cases. Despite some consistency in symptoms across idiopathic and genetic PD cases, tracking progression and treatment response remains an important challenge especially in the development of new therapies. There have been many traditional approaches to tracking including DaTscan imaging, cardiac 123I-MIBG scintigraphy, MRI, CSF analysis, and following clinical symptom progression. Methods: Our previous work showed that peripheral blood mononuclear cells (PBMCs) expressing dopamine transporter (DAT) and tyrosine hydroxylase (TH) in PD patients may correlate with disease progression and with the response to treatment with levodopa. We describe a single case longitudinal follow up of a 40-45-year-old woman with PD who carried a heterozygous TH mutation. We assessed her clinical features over 18 months with DaT scans and immunophenotyping of her PBMCs. Her data were compared with idiopathic PD (n=130 subjects, both sexes) and healthy controls (n=80, age/sex matched). Results: The results revealed a rise in DAT+ immune cells which occurred coincident to documented worsening of her UPDRS-III motor scores. Unlike idiopathic PD patients, following levodopa therapy, the TH+ immune cell levels remained elevated, despite UPDRS-III score improvement. Discussion: The longitudinal immunophenotyping in this PD patient with a TH mutation suggested that DAT+ and TH+ PBMCs could be candidate biomarkers for PD progression and possibly treatment effectiveness. This study provides proof of concept to explore this approach to investigate immunophenotyping in PD progression.

IntroductionSignificant advances have been made in elucidating the pathophysiological mechanisms of Parkinsons disease (PD). Levodopa remains the main therapeutic option -- although it presents heterogeneous clinical benefits among patients. Mutations related to levodopa metabolic pathways have been investigated, but not for mtDNA. Since levodopa metabolism is highly dependent on ionic gradients, endocytosis, and vesicular transport -- all ATP-dependent processes -- the normal function of OXPHOS is essential not only for adequate levodopa metabolism but also for its therapeutic efficacy. This study aimed to analyze levodopa responsiveness profiles considering the mitochondrial genomic component in Brazilian admixed populations. MethodsA total of 49 patients with PD underwent a levodopa challenge test (LCT), followed by whole mitochondrial genome sequencing, pathogenicity prediction of identified variants, and in silico structural analyses. ResultsVariants most frequently affected ND4, ND5, and ND6 subunits in both groups (responsive and non-responsive). Among them, the responsive group presented variants in MT-ND4 (m.12018C>G - T420S) and ND5 (m.13130C>A - P265H) as those with the most significant structural impact, suggesting a loss of the native conformation and alterations in protein efficiency. Additionally, five unique variants were detected only among non-responsive patients, two of which were absent from the dbSNP and ClinVar databases, which indicates the possibility that they are novel variants and potentially population-specific. ConclusionWe provide molecular evidence suggesting that variants in mitochondrial ND4, ND5, and ND6 subunits, in addition to mitochondrial ancestry, may contribute to distinct levodopa responsiveness in PD patients.

ObjectiveTo investigate the genetic etiology of dystonia-parkinsonism among individuals with parkinsonism who have dopamine transporter (DAT) SPECT scans without evidence of dopaminergic deficits (SWEDD). MethodsData for this case-control study were from the Parkinsons Progression Markers Initiative (PPMI) cohort, a multisite observational study. The sample analyzed included participants with whole genome sequencing (WGS) who were diagnosed as Parkinsons disease (PD, n=421), SWEDD (n=64) or healthy controls (HC, n=196). WGS data were analyzed to identify rare pathogenic variants in 30 dystonia-parkinsonism genes. Rare variants were prioritized for those present in individuals with SWEDD, but not in HC, reported pathogenicity in the literature and genetic databases, and with data from programs analyzing variant conservation and effect on protein function. For each SWEDD case with predicted or reported pathogenic variant(s), demographic, clinical, and imaging data were reviewed. ResultsEight of the 64 SWEDD participants (12.5%) had a pathogenic variant in one or more dystonia-parkinsonism genes, including PRKRA, SGCE, GLB1, ADCY5, SLC6A3, and GCDH. Notably, one case had a heterozygous variant in SGCE, p.R263H, which is predicted pathogenic but currently classified as a variant of uncertain significance due to insufficient evidence. ConclusionsPathogenic variants in parkinsonism-dystonia genes occurred in more than 10% of SWEDD cases in the PPMI cohort, supporting the importance of considering dystonia disorders in the differential diagnosis of PD, particularly in the case of participants with normal DAT SPECT scans. Analysis of genetic variants in parkinsonism-dystonia genes in SWEDD cases can provide information which will improve clinical diagnosis and management. KEY MESSAGESO_ST_ABSWhat is already known on this topicC_ST_ABSIndividuals with parkinsonism with scans without evidence of dopamine deficiency (SWEDD) constitute up to 16% of subjects with early parkinsonism referred for inclusion in multicenter observational studies and randomized clinical trials; however, the majority of these individuals do not have Parkinsons disease. Dystonic disorders are high on the list of differential diagnoses for individuals with parkinsonism and SWEDD, and an increasing number of studies support genetic etiologies for dystonic disorders. What proportion of individuals with parkinsonism and SWEDD referred for research studies might carry pathogenic variants in dystonia-parkinsonism related genes is not known. What this study addsThis study identified predicted or reported pathogenic variants in dystonia-parkinsonism related genes in more than 10% of SWEDD cases in the PPMI cohort, supporting the utility of evaluating dystonia-parkinsonism related genetic etiology in SWEDD cases. How this study might affect research, practice, or policyThis study supports the importance of genetic analyses in SWEDD cases which could improve clinical diagnosis and patient management.

ObjectiveIstradefylline, a selective adenosine A2A receptor antagonist, is indicated in the US and Japan as adjunctive treatment to levodopa/decarboxylase inhibitors in adults with Parkinsons disease (PD) experiencing OFF time. This study aimed to observe patterns of dose escalation of levodopa over time in patients initiated on istradefylline. MethodsUsing Japanese electronic health record data, interrupted time series analyses were used to compare levodopa daily dose (LDD, mg/day) gradients in patients before and after initiation of istradefylline. Data were analyzed by period relative to istradefylline initiation (Month 1): pre-istradefylline (Months -72 to 0), early istradefylline (Months 1 to 24), and late istradefylline (Months 25 to 72). Subgroup analyses included LDD before istradefylline initiation (<400, [&ge;]400 to <600, [&ge;]600 mg/day) and treatment with or without monoamine oxidase-B inhibitors (MAO-BIs), catechol-O-methyltransferase inhibitors (COMTIs), or dopamine agonists before istradefylline initiation. ResultsThe analysis included 4026 patients; mean (SD) baseline LDD was 419.27 mg (174.19). Patients receiving [&ge;]600 mg/day levodopa or not receiving MAO-BIs or COMTIs demonstrated a significant reduction in LDD increase gradient for pre-istradefylline vs late-phase istradefylline ([&ge;]600 mg/day levodopa, -6.259 mg/day each month, p<0.001; no MAO-BIs, -1.819 mg/day each month, p=0.004; no COMTIs, -1.412 mg/day each month, p=0.027). ConclusionsThis real-world analysis of Japanese prescription data indicated that slowing of LDD escalation was observed in patients initiated on istradefylline, particularly in those receiving [&ge;]600 mg/day levodopa, suggesting istradefylline may slow progressive LDD increases. These findings suggest that initiating istradefylline before other levodopa-adjunctive therapies may mitigate LDD increases, potentially reducing occurrence or severity of levodopa-induced complications in long-term istradefylline treatment.

BACKGROUNDThere is a need for reliable, objective, and easily accessible biomarkers for Parkinsons disease. OBJECTIVESThe purpose of this study was to screen biomarkers from vital signs and routine blood tests. METHODSLongitudinal data of up to 7 years of vital signs and routine blood tests from 418 patients with Parkinsons disease (PD) untreated at baseline and 185 individuals without any neurological disease were analyzed using linear mixed models. We nominated the biomarkers whose main associations with the measurements were significant as differentiating biomarkers. Similarly, we nominated the interaction effects between biomarkers and time from baseline as progression biomarkers. We tested for 49 biomarkers, and multiple comparison was corrected with the false-discovery-rate of 0.05. We further evaluated the potential biomarkers with regard to their importance in diagnosis prediction and their association with sub-scores on the Movement Disorder Society-Unified Parkinsons Disease Rating Scale (MDS-UPDRS). We also assessed the relationship of the associations using bioinformatics. RESULTSHeart rate, systolic blood pressure, white blood cell fractions, neutrophil counts, serum albumin, sodium and AST were different between PD and controls. The causality or genetic correlations of these biomarkers to PD were not observed. Chronological changes in height, albumin, hemoglobin, and bicarbonate were different in PD. These biomarkers were associated with MDS-UPDRS sub-scores. ConclusionsIn this study, the potential of some easily accessible biomarkers for diagnosis and disease progression was presented. Further investigation of the mechanisms underlying these associations is important for a deeper understanding of the disease and the better management of patients.

L-DOPA Induced Dyskinesia (LID) is associated with prolonged L-DOPA therapy. Vitamin-D receptor modulation improves motor-cognitive deficit in experimental LID Parkinsonism. Therefore, in this study, we investigated the mechanism underlying the anti-dyskinetic potential of Vitamin D3 (VD3). Dyskinesia was induced by chronic L-DOPA administration in 6-OHDA lesioned male C57BL6 mice. The experimental groups (Dyskinesia, Dyskinesia/VD3, and Dyskinesia/Amantadine) and controls were challenged with L-DOPA to determine the abnormal involuntary movements (AIMs) score during 14 days of VD3 (30 mg/kg) or Amantadine (40 mg/kg) treatment. Global behavioral Axial, Limb & Orolingual (ALO) AIMs were scored for 1 min at every 20 mins interval, over a duration of 100 mins on days 1,3,7,11 and 14 of treatment. Thereafter, brain samples were collected and processed for immunoblotting to assess striatal expression of tyrosine hydroxylase (TH), monoamine oxidase (MAO), cathecol-o-methyl transferase (COMT), dopamine decarboxylase (DDC), CD11b, BAX, P47phox, and IL-1{beta}. VD3 significantly attenuated ALO AIMs only on days 11 & 14, with maximal reduction of 32.7% compared with dyskinetic mice but had no effect on days 1, 3 & 7, while amantadine decreased AIMs all through days 1 to 14 with maximal reduction of 64.5%. TH and MAO-B expression were not significantly different across the groups. DDC was significantly suppressed in dyskinetic mice vs control (p<0.001) but remained unchanged in VD3 mice vs dyskinetic mice. COMT was upregulated in the dyskinetic group vs control (p<0.01) and attenuated in VD3 mice (p<0.05) compared to the dyskinetic group. Interestingly, VD3 inhibited significantly (p<0.01) oxidative stress (p47phox), apoptosis (BAX), inflammation (IL-1{beta}), and microglial activation (CD11b) in dyskinetic mice. Overall, we find that the anti-dyskinetic effects of VD3 is associated with modulation of striatal oxidative stress, microglial responses, inflammation, and apoptotic signaling. Impact statementThere are evidences showing that VD3 supplementation improves motor disorders, including Parkinsons disease. We hypothesized that VD3 could improve LID, an abnormal involuntary movement that results from prolonged L-DOPA therapy in the management of PD. We have demonstrated the novel anti-dyskinetic effect of VD3 and associated mechanistic factors in a mouse model of L-DOPA Induced Dyskinesia (LID), which identifies promising targets for dyskinesia therapy.

ObjectiveTo demonstrate that levodopa-unresponsive freezing of gait (ONOFF-FOG), which is a disabling untreatable feature of Parkinsons disease (PD), is distinct from responsive/OFF only FOG (OFF-FOG) and potentially has a distinct pathophysiology.\n\nMethodsFifty-five PD patients completed levodopa challenges after >12 hours OFF with supratherapeutic doses to classify them as NOFOG, OFF-FOG or ONOFF-FOG. Serum levodopa levels ensured threshold levels were met. An \"ON\" response was defined as [&ge;]20% improvement in MDS-UPDRS-III score. Main outcome measure was MDS-UPDRS-III based on clinical exam, timed-up-and-go tests and 360{degrees} turns.\n\nResults45 patients exhibited an \"ON\" response to the challenge. Levodopa-equivalent-dose was 142{+/-}56% of patients typical morning doses. Patients could be classified as: 19 ONOFF-FOG, 11 OFF-FOG, 15 NOFOG. The ONOFF-FOG group exhibited significantly higher NFOG-Q, MDS-UPDRS-II/III scores compared to the OFF-FOG group. MDS-UPDRS-III total varied significantly across medication response states (P<0.01) and groups (P=0.03). Among MDS-UPDRS-III subdomains, significant effects of group (highest in ONOFF-FOG group) were identified for measures of lower extremities and gait. Linear mixed models revealed a highly significant association between serum levodopa level and MDS-UPDRS-III score that did not vary across the groups. There was a highly significant group interaction effect on the association between serum levodopa level with MDS-UPDRS-III item 11 \"Freezing of Gait\" (P<0.001).\n\nConclusionsONOFF-FOG is a distinct subtype of FOG in PD, as opposed to OFF-FOG. This is an important step in demonstrating that FOG is not a single entity and, in turn, could lead to better understanding of pathophysiology and development of effective therapies.

BackgroundGBA variants are the strongest genetic risk factor for Parkinsons disease (PD). However, the pathogenicity of GBA variants concerning PD is still not fully understood. Additionally, the frequency of GBA variants varies widely across populations. ObjectivesTo evaluate Oxford Nanopore sequencing as a strategy, to determine the frequency of GBA variants in Norwegian PD patients and controls, and to review the current literature on newly identified variants that add to pathogenicity determination. MethodsWe included 462 Norwegian PD patients and 367 healthy controls. We sequenced the full-length GBA gene on the Oxford Nanopore GridION as an 8.9 kb amplicon. Six analysis pipelines were compared using two aligners (NGMLR, Minimap2) and three variant callers (BCFtools, Clair3, Pepper-Margin-Deepvariant). Confirmation of GBA variants was performed by Sanger sequencing and the pathogenicity of variants was evaluated. ResultsWe found 95.8% (115/120) true-positive GBA variant calls, while 4.2% (5/120) variant calls were false-positive, with the NGMLR/Minimap2-BCFtools pipeline performing best. In total, 13 rare GBA variants were detected: two were predicted to be (likely) pathogenic and eleven were of uncertain significance. The odds of carrying one of the two most common GBA variants, p.L483P or p.N409S, in PD patients were estimated to be 4.11 times the odds of carrying one of these variants in controls (OR=4.11 [1.39, 12.12]). ConclusionsIn conclusion, we have demonstrated that Oxford long-read Nanopore sequencing, along with the NGMLR/Minimap2-BCFtools pipeline is an effective tool to investigate GBA variants. Further studies on the pathogenicity of GBA variants are needed to assess their effect on PD.