Parkinsonism & Related Disorders

We investigated whether people with Parkinson's disease who are dual GBA1+LRRK2 carriers have a milder, LRRK2-like phenotype as previously reported. This was accomplished by comparing clinical features and alpha-synuclein seed amplification assay (SAA) positivity rates between dual GBA1+LRRK2-PD(n=13), GBA1-PD(n=169) and LRRK2-PD(n=175) carriers in a cross-sectional retrospective study of Parkinson's Progression Markers Initiative (PPMI) data. Our results show that GBA1+LRRK2-PD rate(83%) is closer to GBA1-PD rate(87%) rather than LRRK2-PD rate (62%mp-value>0.05). GBA1+LRRK2-PD have both non-motor and motor phenotypic similarity of GBA1-PD(p-value>0.05). This small PPMI cohort indicates that dual GBA1+LRRK2-PD carriers' SAA positivity and phenotype are aligned with GBA1-PD.

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSExcessive or unregulated iron in the brain can lead to toxicity via ferroptosis and related mechanisms. Iron accumulation in the substantia nigra (SN) occurs with Parkinsons disease (PD) progression and has been hypothesized to be an etiological mechanism. ObjectiveBased on emerging clinical observations, we tested the hypothesis that iron accumulation in the SN is a consequence of levodopa administration and is treatment-related rather than an intrinsic etiological mechanism. MethodsWe used both unilaterally lesioned 6-OHDA and unlesioned rats. We administered levodopa to rats at doses that were allometrically calculated to be similar to those used in mid-stages of PD. Iron-sensitive MRI (R2*) was used to quantify iron in the brain. Both group and intra-subject analyses were done using paired t-tests and linear mixed models. ResultsExperiment 1 used the unilateral 6-OHDA model to take advantage of the almost complete lack of dopamine neurons on the lesioned side. This permitted testing if levodopa-induced iron accumulation occurred in and/or depended on dopamine neurons. Fifteen days of levodopa treatment caused a marked increase in Fe in both the lesioned (p = 0.042) and unlesioned sides (p = 0.005), showing that iron accumulation does not depend on the presence of dopamine neurons. Based on these data, in experiment 2 unlesioned rats were administered levodopa daily for four months, and iron (R2*) values were assessed at baseline, 1, 2, and 4 months. In these normal rats, the levodopa-treated group had significantly increased Fe (R2*) in the substantia nigra compared to the vehicle group (p = 0.013). Interestingly, these effects were limited to the striatum, with no increases seen in the striatum, ventral tegmental area, or frontal cortex ConclusionLevodopa triggers processes that increase iron deposition in the substantia nigra, but this process may not depend on dopamine neurons. The underlying mechanisms and the effect on PD progression are important to elucidate and may transform how we understand PD and related neurodegenerative disorders

Background Neuropsychiatric fluctuations in Parkinson's disease (PD) often accompany motor fluctuations, but their temporal relationship during the acute levodopa response remains unclear. Objectives To determine whether motor and neuropsychiatric responses occur synchronously during the OFF-to-ON transition. Methods Nineteen fluctuating PD patients underwent a high-resolution levodopa challenge with repeated assessments every 10 minutes for 60 minutes after levodopa administration. Motor symptoms (akinesia, rigidity) and neuropsychiatric fluctuations were quantified. Transition times (t25%-t50%-t75%-t100%) and response profiles were analyzed using correlation and clustering approaches. Results Motor and neuropsychiatric transition times were not correlated at any threshold (all FDR-corrected p>0.05; Bayes factors <1), supporting temporal dissociation. Among 18 patients with complete data, clustering revealed synchronous (6/18), neuropsychiatric-preceding (7/18), and motor-preceding (3/18) profiles. Conclusion Motor and neuropsychiatric responses to levodopa during PD fluctuations are partly independent and follow heterogeneous, patient-specific temporal profiles, supporting the search for distinct biomarkers and future individualized adaptative therapies

Objective To map national Parkinsons disease (PD) research capability to inform an inclusive delivery strategy for a large-scale clinical trial. Background Few people with PD participate in clinical trials, particularly from under-served populations. The Edmond J Safra Accelerating Clinical Trials in PD initiative (EJS ACT-PD) aims to deliver an inclusive multi-arm multi-stage (MAMS) disease modification PD trial. Methods A survey disseminated to National Health Service (NHS) hospitals assessed PD research capability regarding trial experience, rater expertise, trial facilities and specialist investigations. A process was developed to categorise sites into 3 tiers, with tier 1 having the least PD-research capability or experience, and tier 3 being experienced specialist centres. We mapped tiers to PD prevalence, social deprivation and ethnic diversity to identify infrastructure gaps. We developed trial delivery strategies to facilitate rapid and inclusive recruitment. Results Out of 97 survey responses, 43 sites were categorised as tier 1, 33 as tier 2 and 21 as tier 3. Diversity and social deprivation index were higher for tier 3 sites (predominantly urban). A greater proportion of tier 1 and 2 sites were situated in areas of higher PD prevalence (predominantly rural). Ninety one percent of sites reported experience with remote trial delivery methods. Our delivery strategy included: initial trial set-up at tier 3 sites to enable rapid and ethnically diverse recruitment; core funded staff within strategic sites to develop regional solutions for inclusive trial participation and to enable research opportunity provision in areas where currently very little exists, and a hybrid delivery model of in-person and remote study visits, ensuring maximal acceptability and deliverability. Conclusions The mapping of current PD research delivery capability has allowed us to develop a trial delivery strategy that will broaden the provision of research participation opportunity to under-served groups. It has also enabled existing infrastructure to be maximised while mitigating identified gaps.

BackgroundHeterozygous mutations in the GBA1 gene encoding the enzyme glucocerebrosidase (GCase) represent the most common genetic risk factor for developing Parkinsons disease (PD). The underlying mechanisms by which GBA1 mutations lead to PD through both loss- and gain-of-function effects remain unclear. There is a strong rationale for the generation and characterisation of a humanised GBA1 mouse model to allow the effect of GBA1 mutations on GCase function to be studied within the context of the human protein. MethodsWe have generated novel humanised mutant GBA-L444P and wild type GBA-WT mouse models using BAC recombineering and site-specific integration allowing the incorporation of the whole GBA1 locus as a transgene, including the endogenous promoter, all exons and introns, and flanking regions. Our experimental design crossed each GBA1 transgene onto a Gba+/- background and included Gba+/- littermate controls in our cohorts, allowing us to explore both the loss- and gain-of-function of GBA1 mutations. We have carried out "deep phenotyping" to characterise these mice by biochemical, stereological and behavioural testing, and assess dopamine release and content using fast-scan cyclic voltammetry and high performance liquid chromatography. ResultsThe GBA-L444P mice showed a significant reduction in GCase activity by 18 months of age and preferentially expressed a high molecular weight form of the GCase protein, likely due to retention in the ER and aberrant glycosylation. The GBA-L444P, but not Gba+/-, mice demonstrated an early and persistent reduction in dorsal striatal dopamine release in the absence of any dopaminergic cell loss or deficits in dopamine synthesis or reuptake, compared to human wild-type controls. GBA-L444P and Gba+/- mice developed an accumulation of oligomeric -synuclein pathology, but only GBA-L444P mice demonstrated subtle but significant changes in behaviour. ConclusionsThe novel humanised GBA-L444P mouse model described here helps to resolve gain- or loss-of-function effects of GBA1 mutations seen in Parkinsons as well as providing a novel set of models to investigate the human protein. Our work demonstrates that changes in dopamine release and behavioural deficits arise from a gain-of-function mechanism, whereas -synuclein pathology arises from GCase loss-of-function.

Background: Gait variability is a hallmark of Parkinson's disease (PD) and has been linked to cognitive deficits and fall risk. Rapid eye movement sleep behavior disorder (RBD) is a strong predictor of synucleinopathies, yet evidence for gait changes in RBD is inconsistent. Performing a dual task increases gait variability, an effect that can be quantified using a cost function. Objective: Determine the degree to which dual task cost differs between control, RBD, and PD participants at baseline, and between RBD converters versus non-converters at follow-up. Methods: 46 RBD, 23 control, and 14 PD participants completed standardized gait analysis at baseline. Parameters chosen for analysis included enhanced gait variability index (eGVI), functional ambulation performance (FAP), velocity, step length, cadence, base of support, and double support time. Medical records were surveilled for 3 years following participant enrollment, determining that 6 RBD participants converted to PD or dementia. Baseline gait indices and dual task costs were compared between control, RBD, and PD groups at enrollment, and between RBD stable and RBD converters at follow-up. Results: The PD group had greater eGVI, as well as greater dual task cost for FAP, cadence, width, and double support time. No differences in gait variability were identified between RBD and control groups at baseline. Compared to the stable group, RBD converters had greater dual task cost for FAP, velocity, cadence, and double support time. Conclusions: Increased gait variability during dual task may identify RBD patients at imminent risk of phenoconversion.

Background: The clinical applicability of large language models (LLMs) in Parkinson's disease (PD) management remains insufficiently characterized, particularly in generative responses to clinical vignette scenarios. Objective: To evaluate the quality of clinical assessments and management plans generated by a general-purpose LLM (Gemini 1.5 Pro) and a medically specialized LLM (OpenEvidence), and to compare their performance. Methods: Models generated free-text responses to 45 open clinical queries, focused on assessment of the situation, and recommended management plan. Two movement disorders fellows rated outputs using 5-point Likert scales, dichotomized into clinically appropriate ([&ge;]4) versus inappropriate ([&le;]3). Discrepancies were adjudicated by a senior movement disorders specialist. Paired comparisons used McNemar's test; qualitative analysis examined severe errors. Results: Gemini 1.5 Pro and OpenEvidence showed high rates of clinically appropriate assessments (80.0% vs. 86.7%) but lower performance in management plans (48.9% vs. 57.8%). Cases in which both assessment and plan were clinically appropriate occurred in 46.7% and 55.6% of cases, respectively. None of these differences reached statistical significance. Severe errors were uncommon in assessments (6.7% vs. 8.9%) but more frequent in plans (26.7% in both), predominantly reflecting treatment strategy errors. Conclusions: In generative clinical reasoning tasks involving Parkinson's disease management vignettes, LLMs demonstrated reasonable performance in assessment, but consistent limitations in plan generation. The medically specialized LLM demonstrated several qualitative advantages but no statistically significant performance benefit over the general-purpose model. Therefore, these tools should be used with appropriate caution in Parkinson's disease management, particularly regarding treatment recommendations.

Background: Freezing of gait (FOG) in Parkinson's disease (PD) is provoked by turning, doorways and dual-task walking. We evaluated WALK, a cadence-linked vibration neuromodulation combined with motor-learning training. Methods: Single-centre, sham-controlled pilot randomised trial. Adults with PD (Hoehn and Yahr 2 to 4) and neurologist-verified FOG were randomised 1:1 to intervention (WALK; vibration enabled) or sham (WALK; vibration disabled), alongside identical supervised home-based training for 6 weeks (3 sessions per week). OFF-medication assessments were performed at S0, S8 and S16. At S8 and S16, assessments were completed without a device and then with a device (fixed order). The primary endpoint was the mZ-FOG total (0 to 36). Results: Forty participants completed follow-up assessments (intervention n=24; sham n=16) with 100% session adherence and no serious device-related adverse events. In the intervention group, mZ-FOG total improved when assessed with the device at S8 ({Delta}=8.08) and S16 ({Delta}=9.21) relative to S0, with partial retention when assessed without the device at S16 ({Delta}=5.54). Conclusions: Cadence-linked, localised vibration neuromodulation plus motor-learning training was feasible and was associated with clinically meaningful within-intervention-group reductions in FOG. Taken together, the effect sizes and task-specific pattern support progression to a multicentre, assessor-blinded trial with an active sham, powered for between-group comparisons and durability and/or adherence endpoints.

Importance: The real-world prevalence and the clinical determinants associated with cognitive impairment in diverse patients with Parkinson disease (PD) have been understudied. Objective: To determine the prevalence of cognitive impairment in a diverse PD cohort and explore associations with vascular, motor, and nonmotor factors. Design, setting and participants: Case-only analysis of diverse patients with PD recruited to the East London Parkinson disease project (July 2022 to July 2025) at the Royal London Hospital, a tertiary referral center. Of 237 patients with cognitive status defined by expert, multi-disciplinary, clinical consensus, 223 remained after excluding atypical or secondary parkinsonism, other dementias, and study withdrawal. Exposures: Observational study (no experimental intervention); exposures included vascular risk factors, motor and nonmotor clinical features. Main Outcome(s) and Measure(s): The main outcome was cognitive impairment (PDCI), defined as mild cognitive impairment (PDMCI) or dementia (PDD) by expert clinical consensus based on clinical, imaging, and cognitive screening. Results: Among 223 participants with a median disease duration of 4.0 (1.0-9.0) years, 112 (50.2%) had PDCI, including 62 (27.8%) with PDD and 50 (22.4%) with PDMCI. South Asian ethnicity was associated with PDCI in univariate analysis (OR, 2.30; 95% CI, 1.32-4.00, P = .003) and the association strengthened after adjusting for age, gender, years of education, disease duration and depression scores (OR, 3.60; 95% CI, 1.68-7.69, P < .001). PDCI was associated with increased odds of smoking (OR, 3.62; 95% CI, 1.56-8.41, P = .003) in the adjusted model. Increased odds were also associated with motor severity (Movement Disorders Society Unified Parkinson Disease Rating Scale Part III; OR per point increase 1.07; 95% CI, 1.04-1.10; P < .001), and daytime somnolence score (Epworth Sleepiness Scale; OR per point increase, 1.08; 95% CI, 1.01-1.16; P = .03). Conclusions and Relevance: In this multi-ethnic study of PD using gold-standard expert multidisciplinary consensus, cognitive impairment was common and more prevalent among South Asian individuals. Smoking, greater motor severity, and higher daytime somnolence were associated with increased odds of cognitive impairment.

As genetic testing becomes increasingly integrated into Parkinson disease (PD) research, including targeted testing for variants in LRRK2 and GBA1, the return of individual research results is becoming more common. However, limited qualitative data exists regarding how research participants experience genetic results disclosure and post-test genetic counseling in PD research settings. We conducted semi-structured qualitative interviews with participants (n=13) enrolled in the Parkinson Precision Medicine Initiative (formerly Parkinson Progression Markers Initiative; PPMI) who had received PD-related genetic test results and post-test genetic counseling. Interviews were conducted 1 to 3 weeks following result disclosure and analyzed using thematic analysis with a primarily deductive coding approach informed by study aims and inductive identification of emergent themes. Four primary themes were identified: (1) personal connection and motivations for participation, (2) centrality of result disclosure and information preferences, (3) emotional experiences and support needs, and (4) communication quality and alignment with participant needs. Overall, our findings underscore the importance of person-centered genetic counseling within PD research. As return of genetic and biomarker results in research and clinical trial contexts expand, thoughtful integration of relational, informational, and communication-focused practices will be essential to support participant engagement and trust.

Background Sleep disturbances affect up to 60-80% of people with Parkinsons disease (PD) and are associated with worse clinical outcomes and reduced quality of life. Dyskinesia is a common motor complication of dopaminergic therapy, but its relationship with sleep quality remains incompletely defined. Methods Forty-seven people with PD (median age 68 years; 44.7% female; median disease duration 5 years; 38.3% from non-White ethnic background) were assessed for sleep quality on Pittsburgh Sleep Quality Index (PSQI). Dyskinesia was assessed using Movement Disorder Society-Unified Parkinsons Disease Rating Scale (MDS-UPDRS) Part IV items 4.1 and 4.2, and 7-day wearable monitoring with the Parkinsons KinetiGraph (PKG) to derive median dyskinesia score (DK_50) and fluctuation dyskinesia score (FDS). All analyses were conducted using multivariate regression. Associations with sleep quality were adjusted for age, sex, and disease severity (MDS-UPDRS Part III) in Model A; additionally for levodopa equivalent daily dose (LEDD) in Model B; and further for disease duration in Model C. Results In Model A, all four dyskinesia measures were significantly associated with sleep quality. After adjusting for LEDD in Model B, only DK_50 remained a significant predictor of worse sleep (B=0.18, 95CI: 0.003-0.357, P=0.047). With additional adjustment for disease duration in Model C, the association for DK_50 was attenuated (B=0.18, 95%CI: -0.001 to 0.356, P=0.051). Conclusions Wearable-derived continuous dyskinesia burden was independently associated with worse sleep quality, whereas clinician-rated dyskinesia was not, highlighting the added clinical value of objective motor monitoring in PD. Disease duration may partly confound this relationship. Larger prospective studies are warranted.

Background: Parkinson's disease (PD) has a prolonged prodromal phase during which non-motor symptoms (NMS) may emerge years before the appearance of classical motor signs. This makes NMS a promising and clinically accessible source of information for early risk stratification. Objective: In this study, we investigated whether NMS alone can serve as reliable predictors of PD risk using clinical data from the Parkinson's Progression Markers Initiative (PPMI) cohort. Methods: We developed a stacked ensemble machine learning framework that integrates feature-level modelling, a global multivariate model, and a patient-similarity component to capture complementary patterns within NMS profiles. The model was trained using leakage-controlled patient-level validation and evaluated on an independent held-out test set. Results: The final ensemble achieved strong predictive performance, with an area under the ROC curve of 0.955, sensitivity of 0.929, and specificity of 0.900. Explainability analysis further showed that olfactory dysfunction, gastrointestinal symptoms, urinary and other autonomic features, and selected cognitive measures were among the most influential predictors. These findings support the hypothesis that NMS are not merely associated features of PD, but can function as meaningful predictors of disease risk even without imaging or biomarker inputs. Additionally, the final validated model is implemented as a web-based research prototype to demonstrate real-time translational feasibility. Conclusion: Overall, this study highlights the predictive value of NMS for PD risk assessment and supports their use in research-oriented early screening frameworks.

Background: Higher iron occurs in the substantia nigra in Parkinson's disease (PD), but its behavior over time is poorly understood. Objective: To determine if nigral iron measured by quantitative susceptibility MRI can track progression of early stages of PD. Methods: Thirty-four early-stage PD patients (disease duration < 4 yrs) and 35 matched controls were recruited. Iron content in the substantia nigra and related regions was obtained using quantitative susceptibility mapping with zero-referencing at both baseline and one-year follow-up, along with clinical metrics. Results: Of five clinic metrics and five regional iron measures, only MDS-UPDRS II (p = 0.046) and SNc iron (p = 0.004) showed significant changes for PD subjects in the one-year epoch. The changes of SNc iron also were correlated with changes of MDS-UPDRS II (p = 0.005). Conclusion: Nigral iron content measured by zero-referencing is sensitive for tracking disease progression in early-stage PD.

Background: PD GENEration (NCT04057794, NCT04994015), sponsored by the Parkinson's Foundation in partnership with Aligning Science Across Parkinson's (ASAP) through the Global Parkinson's Genetics Program (GP2), is an international, observational, clinical research study that offers genetic testing and counseling to people living with Parkinson's disease (PwP) at no cost. PD GENEration has aimed to empower PwP and their clinicians with knowledge of their genetic status, to accelerate recruitment into precision medicine trials, and to advance research through data sharing. Since its launch in 2019, the study has expanded to enroll over 32,000 PwP (as of March 31, 2026), from 10 countries across North, Central, and South America, the Caribbean, and Israel. Methods: Over the course of 6 years, PD GENEration has evolved to accommodate the growing scientific and research needs of the Parkinson's community while also increasing the ability to return genetic test results to PwP at a greater scale. Participants with a diagnosis of Parkinson's disease (PD) may enroll in-person or virtually where informed consent and blood sample collection can occur. Samples are analyzed at a College of American Pathologists/Clinical Laboratory Improvement Amendments (CAP/CLIA)-certified laboratory using whole genome sequencing, with variants curated for a primary panel of seven PD-associated genes. Results are disclosed during a genetic counseling visit, where further testing is offered for two optional additional gene panels. Those who consent undergo analysis of additional genes, and results are returned during a genetic counseling visit for those that test positive for a variant. In addition to returning genetic results to PwP, a central pillar of the study design has been the open sharing of genomic data to advance discovery in PD research in partnership with ASAP and GP2. Discussion: PD GENEration applies a flexible framework, allowing for country specific considerations and the integration of multiple site models, evolving based on participant needs and the prioritization of equity and accessibility. We summarize PD GENEration's implementation and scaling, highlight key accomplishments and lessons learned, and provide guidance for those interested in implementing large-scale clinical genetic testing studies across other diseases and therapeutic domains.

Background: Mono-allelic Dehydrodolichyl Diphosphate Synthase (DHDDS) variants are associated with juvenile Parkinsonism, developmental delay and seizures. Symptoms are progressive, and various mechanisms, such as defective glycosylation, lysosomal dysfunction and cholesterol accumulation have been hypothesized to underlie disease symptoms. There is no treatment for DHDDS-related disease. Methods: Patient-derived cortical forebrain organoids were created to elucidate disease mechanisms and evaluate potential treatments. In these neuronal models, glycosylation, lipidomics, proteomics, cholesterol/ganglioside accumulation, mitochondrial function and electrophysiological activity were assessed. Finally, we investigated the effects of nicotinamide mononucleotide (NMN), identified through a yeast-based drug screen, in neuronal cell models and in six patients in an off-label, N-of-1, observational series. Results: DHDDS-patient derived organoids showed visual signs of degeneration after four months of culturing. This was accompanied by significant cholesterol accumulation in astrocytes, decreased mitochondrial respiration and loss of deep-layer neurons. In addition, we identified glycosylation abnormalities, showing for the first time that glycosylation in human tissue is affected by monoallelic DHDDS variants. Proteomic analysis revealed altered protein expression of proteins involved in lipid metabolism, cytoskeletal organization and neuronal development. We found that oral Nicotinamide Mononucleotide supplementation led to significant improvement in mitochondrial respiration and electrophysiological parameters in organoids, concurring with clinical improvements in all of the treated patients, particularly regarding their ataxia and tremor. Conclusion: Our findings reveal a progressive phenotype in DHDDS-patient-derived brain organoids, with mitochondrial dysfunction and astrocyte-specific metabolic alterations contributing to disease pathology. Notably, NMN treatment led to clinical improvements in patients with heterozygous DHDDS variants, highlighting its potential as a therapeutic strategy.

PurposeParkinsons disease (PD) is a neurodegenerative disease that affects motor control but can also influence sensory perception. Changes in vision and proprioception are well-documented but less is known about how PD alters auditory perception, particularly perception of speech acoustic properties. The current study examined perception of speech rate and intensity in PD and the relationship of auditory perception to disease severity. MethodPeople with PD were compared to age- and hearing-matched controls using perceptual tasks focused on discrimination and learning of speech rate and intensity. For rate discrimination, speech, non-speech, and visual stimuli were included to determine whether performance differences for PD participants and controls were specific to speech. Disease severity was assessed using the MDS-Unified Parkinsons Disease Rating Scale (MDS-UPDRS) and the relationship to performance on perceptual discrimination and learning tasks was evaluated. ResultsPeople with PD performed significantly worse than controls in the rate discrimination task for all types of stimuli. There were no significant group differences for intensity discrimination. However, participants with greater PD disease severity demonstrated significantly poorer intensity discrimination accuracy. Performance on learning tasks utilizing rate and intensity manipulations did not differ between PD and control participants and was unrelated to PD disease severity. ConclusionsPeople with PD had difficulty discriminating rate differences across speech, non-speech, and visual stimuli, indicating that challenges with rate perception are not limited to speech. The relationship between intensity discrimination and disease severity suggests common dopaminergic networks between motor symptoms and auditory perception in PD.

Increased iron in the substantia nigra has been thought to be a mechanism potentially related to the etiology and/or progression of Parkinson's disease (PD). We hypothesized that genetic variants of HFE, a major iron regulatory gene, would influence substantia nigra iron accumulation in PD. The HFE genotype was obtained from 195 subjects (102 PD and 83 Controls) who participated in the PD biomarker program (PDBP) in central Pennsylvania, United States. For this study, carriers of two SNPs (HFE H63D and/or C282Y) were considered as variants and the others as wildtype. Susceptibility MRI metrics (QSM, R2*) were assessed at baseline, 18, and 36 months. The primary region of interest was the substantia nigra, the key pathology focus of PD. Group differences in substantia nigra QSM and R2* between HFE variants carriers and wildtype were compared between PD patients and controls at baseline and in progression over time using linear mixed-effects model. We also used interaction analyses to explore if HFE genotype impacts clinical measures of PD progression. Of the 102 PD patients, 72 were wildtype, and 30 HFE variant. Of the 83 controls, 56 were wildtype and 27 were HFE variants. There was a total of 451 data points available for analysis. Compared to wildtype patients, patients with HFE variants showed higher baseline substantia nigra QSM (p=0.006), but not higher R2* (p=0.487). Controls had no HFE-dependent differences. Longitudinally, substantia nigra QSM and R2* increased significantly over both 18- and 36-months regardless of HFE status (p's<0.05). Compared to wildtype, PD subjects with HFE variants showed an overall faster increase in R2* (p=0.004) and QSM (p=0.003) over the total 36-month epoch, and this reached the statistical significance for R2* during the first 18-months (p=0.026) and for QSM in 36-months (p=0.005). HFE status showed a significant interaction with motor scales [MDS-UPDRS II (p=0.006), III (p=0.0002)], suggesting a faster symptomatic progression in PD patients with HFE variants compared to wildtype. Although HFE genotype has been shown not to associate with the occurrence of PD, these data demonstrate for the first time that in PD patients substantia nigra iron accumulation and disease progression are affected by HFE genotype. The underlying mechanisms may be important in the progression of PD and the development of personalized treatment.

Background: Reliable biomarkers for Parkinson's disease (PD) pathology detection are essential for research. The alpha-synuclein (aSyn) seed amplification assay (SAA) is a validated biomarker for misfolded aSyn. Objectives: To assess the association between aSyn SAA and LRRK2-related PD (LRRK2-PD) and its link to mitochondrial genetic burden. Methods: We included N=76 LRRK2 p.Gly2019Ser variant carriers (N=22 affected, N=54 unaffected), N=714 patients with idiopathic PD (iPD), and N=411 controls from Norway. We analyzed cerebrospinal fluid (CSF)-based aSyn SAA in N=10 PD patients and N=30 unaffected LRRK2 p.Gly2019Ser carriers, alongside N=6 controls and N=56 iPD patients. A mitochondrial polygenic score (MGS) was derived from genotyping data, using PPMI as an additional cohort (iPD: N=355, LRRK2-PD: N=118). Results: Seeding was observed in 80% of patients with LRRK2-PD, and in one unaffected variant carrier (AUC=0.97, CI 0.92-1.00). In a meta-analysis across two PD cohorts, higher MGS was associated with increased aSyn seeding (pooled beta=0.38, p=0.028). Conclusions: CSF-based aSyn SAA can discriminate between LRRK2-PD and unaffected carriers. Our findings support an association with mitochondrial burden and aSyn seeding.

In both preclinical and clinical studies, transfusions of plasma from young individuals have been reported to ameliorate aspects of neurodegeneration. This study was designed as a preliminary test of the hypothesis that plasma transfusions from young donors might benefit Parkinson's patients. 19 patients were allocated to receive either 2-liters of plasma from young donors, in two doses spaced two days apart, or two doses of placebo. For the next 24 weeks, this double-blind study evaluated changes on a modified MDS-UPDRS scale, along with blood tests and other observations. Adverse events possibly related to transfusion were mild rise in blood pressure and urticaria. A t-test on the changes in the sum of UPDRS subscales 1-3 showed that the plasma patients did better than the placebo patients (p = 0.03*). For patients given yFFP (young Fresh Frozen Plasma), the estimated decrease in the sum of scales 1-3 was 7.1 (95% conf. interval 4.3 to 9.9). Our results give a preliminary indication that young plasma transfusions reduce Parkinson's symptoms and have a place in treatment of these patients. (NCT 04202757).

Background: Deep brain stimulation (DBS) of the ventral intermediate nucleus and posterior subthalamic area (VIM/PSA) in Essential Tremor (ET) and the subthalamic nucleus (STN) in Parkinson's disease (PD) are established treatment for tremor. To achieve maximum tremor control, increasing stimulation frequency beyond 130 Hz is part of clinical practice, but lacks scientific evidence. Objective: To compare tremor suppression under total electrical energy delivered (TEED)-equivalent stimulation at 130 Hz versus 185 Hz in STN-DBS for PD and VIM/PSA-DBS for ET. Methods: In this prospective, double-blind study, acute DBS effects were assessed in 18 people with ET (n = 29 hemispheres), and 25 people with PD (n = 30 hemispheres). Tremor-suppressive effects, evaluated by accelerometry, were compared with TEED-equivalent stimulation at 130 Hz and 185 Hz using linear mixed-effects models, explorative pairwise comparisons, and equivalency testing. Results: Linear mixed-effects models revealed no significant effect of stimulation frequency on tremor improvement in both cohorts. Pairwise comparisons showed no consistent differences in total tremor improvement with TEED-equivalent 185 Hz vs 130 Hz DBS. Post-hoc equivalence testing confirmed equivalence of stimulation frequencies under TEED-equivalent conditions within a +/- 20% margin of relative tremor improvement. Conclusion: This study provides Level II evidence that a higher stimulation frequency of 185 Hz does not offer additional benefit in deep brain stimulation for tremor and supports 130 Hz as the standard stimulation frequency for tremor suppression in ET and PD.