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.

BackgroundEffective screening for Parkinson disease (PD) is important for both symptomatic treatment and recruitment into intervention trials. We recently developed a toolkit to quantify PD risk. Here, we examined the PREDIGT models diagnostic performance when deployed at home. MethodsWe contacted 613 subjects following outpatient clinic encounters. Between 2022-2024, 305 participants (range, 40-85 years) were recruited: 93 with typical PD; 66 had other neurological diseases (OND); 146 were neurologically healthy. Two versions of the toolkit were completed: First, an original, 69-item-long questionnaire paired with a 40-scent smell test; thereafter, a simplified, 11-item-long questionnaire and a newly developed, 8-scent smell test. PREDIGT summary scores were calculated for each subject to examine diagnostic classifications. Area-under-the-ROC-curve, sensitivity, specificity, and likelihood ratios were used to evaluate performances and to determine clinically relevant thresholds. ResultsIn both versions, PD patients had higher questionnaire scores and lower smell test scores than neurologically healthy controls (p<0.001); scores for OND subjects ranked at intermediate levels. The simplified questionnaire outperformed the original version in diagnostic accuracy. The abbreviated smell test performed as well as the 40-item version in identifying hyposmia. At a value of 22.94 (range 0-100) for the threshold that separates PD subjects from other participants, the simplified PREDIGT summary score showed a sensitivity of 0.98, a specificity of 0.83, and revealed positive and negative likelihood ratios of 5.88 and 0.02, respectively. InterpretationOur study reveals that unsupervised screening for typical PD can be effectively carried out at home using an 11-item questionnaire and 8-scent smell test.

BackgroundParkinsons disease (PD) is a progressive neurodegenerative disorder with complex pathophysiology. The potential of integrating biomarkers of neuronal injury, neuroinflammation, and modulators of Wnt signaling for PD diagnosis remains largely unexplored. ObjectiveThis study aimed to evaluate the diagnostic and clinical predictive value of a ten-biomarker serum panel encompassing markers of neuronal injury (NSE, UCHL1), neuroinflammation (GFAP, HMGB1), synaptic plasticity (BDNF), proteinopathy (-Synuclein, {beta}-Amyloid-42), and Wnt signaling (R-spondin-1, DKK1, Sclerostin), with a particular focus on chronic fatigue in PD. MethodsIn this case-control study, 90 PD patients and 45 healthy controls were enrolled. Serum biomarkers were quantified using ELISA. Clinical severity was assessed using the Movement Disorder Society-Unified Parkinsons Disease Rating Scale (MDS-UPDRS) and Fibro-Fatigue (FF) scales. Binary logistic regression and multiple linear regression analyses were used to evaluate the diagnostic and predictive value of biomarkers for PD diagnosis, psychiatric and motoric scores, and an FF score reflecting chronic fatigue syndrome (CFS) severity. ResultsA model incorporating NSE, DKK1, and {beta}-Amyloid-42 effectively discriminated PD patients from controls, yielding an area under the curve (AUC) of 0.932 and an overall accuracy of 83.0%. NSE and DKK1 emerged as the main predictors of overall disease severity, motor symptoms, and CFS severity. Regression analyses indicated that 41.3% of the variance in the FF score was explained by increased NSE, DKK1, {beta}-amyloid, and UCHL1, while 42.9% of the variance in psychiatric symptoms was explained by increased NSE, DKK1, and {beta}-amyloid. Increased GFAP levels were significantly associated with motor dysfunction. ConclusionThe combined presence of neuronal injury, Wnt signaling dysregulation, and amyloid pathology may represent a key pathophysiological component underlying PD, CFS-like fatigue, and psychiatric symptoms in PD. Targeting neuronal injury and Wnt signaling pathways may offer novel therapeutic strategies for managing fatigue and psychiatric manifestations in 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.

IntroductionMotor complications are major determinants of disability in Parkinsons disease (PD), yet clinician-rated motor complication severity does not fully explain variability in health-related quality of life (HRQoL). Research questionTo examine the contribution of illness perceptions and cognitive-behavioural responses to HRQoL alongside motor complication severity in people with PD. MethodsThis multi-centre, cross-sectional study recruited 58 people with idiopathic PD (median age 68 years; 55.2% male; 48.3% from minoritised ethnic backgrounds; Hoehn & Yahr stage 2-3). All underwent assessment of motor complications (Movement Disorder Society-Unified Parkinsons Disease Rating Scale; MDS-UPDRS Part IV) and HRQoL (Parkinsons Disease Questionnaire-39 Summary Index; PDQ-39 SI). Illness perceptions were measured with Illness Perception Questionnaire-Revised (IPQ-R) Part 2, and cognitive-behavioural responses with Cognitive and Behavioural Responses Questionnaire (CBRQ). Regression models were adjusted for age, sex, disease duration, motor severity (MDS-UPDRS Part III), levodopa equivalent daily dose (LEDD), anxiety, depression, and cognitive function. A subset (n=47) completed 7-day Parkinsons KinetiGraph monitoring. ResultsDemographic and clinical covariates explained 77.3% of variance in HRQoL (R{superscript 2}=0.773). Adding motor complication severity explained a significant additional 3.7% ({Delta}R{superscript 2}=0.037, P=0.004). Subsequent inclusion of illness consequences (IPQ-R) and catastrophising (CBRQ) explained a further 4.1% ({Delta}R{superscript 2}=0.041, P=0.004), yielding a final adjusted R{superscript 2} of 0.815. In the fully adjusted model, catastrophising (B=0.797, P=0.027) and perceived consequences (B=0.767, P=0.013) remained independently associated with HRQoL. ConclusionHRQoL in PD appears to depend not only on motor complication severity, but also on patients interpretations and responses. Clinicians should assess both to guide holistic care and support adaptive coping.

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.

ObjectiveTremor is a common motor symptom of Parkinsons disease (PD) that reduces quality of life. Cortico-cortical paired associative stimulation (ccPAS) is a transcranial magnetic stimulation protocol that induces connective associative plasticity between cortical regions. This study investigated the effects of ccPAS over supplementary motor area (SMA) and primary motor cortex (M1) on SMA-M1 facilitation and tremor severity in individuals with tremor-dominant PD. MethodsFourteen individuals with tremor-dominant PD (mean age 66.5 {+/-} 6.3 years; 5 females) received real and sham ccPAS in separate sessions. SMA-M1 activity and tremor severity were measured before and after ccPAS. Participants were tested OFF dopaminergic medication. ResultsSMA-M1 facilitation increased significantly after real but not sham ccPAS. There was no significant change in tremor severity after either real or sham ccPAS. Tremor severity was not associated with the change in SMA-M1 activity following ccPAS or with baseline SMA-M1 activity. ConclusionsccPAS can increase SMA-M1 facilitation in individuals with tremor-dominant PD. A single session of SMA-M1 ccPAS was insufficient in modulating tremor severity. SignificanceThis study provides preliminary evidence of significant increases in SMA-M1 facilitation from ccPAS in tremor-dominant PD OFF dopamine medication. Future research should explore ccPAS effects ON dopamine medication, and the effects of multi-session ccPAS.

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.

BackgroundVariants in GBA1 are important genetic risk factors for synucleinopathies, including Parkinsons disease (PD). While several GBA1 variants are established risk or severity modifiers, the role of the p.E427K variant remains unclear. ObjectiveTo determine whether the GBA1 p.E427K variant is associated with risk of synucleinopathies. MethodsWe performed a meta-analysis of case-control studies reporting the frequency of GBA1 p.E427K (p.E388K) in PD and related synucleinopathies. Data were obtained from published studies, open-access resources, and large cohorts, including in-house datasets. Odds ratios (ORs) were calculated for each cohort and pooled using a random-effects model. ResultsAcross 67,484 patients and 124,079 controls, GBA1 p.E427K was associated with increased disease risk (pooled OR = 1.87, 95% CI 1.28-2.72, P = 0.001). Enzymatic data showed reduced glucocerebrosidase activity in carriers. ConclusionsThe GBA1 p.E427K variant is a risk factor for synucleinopathies and should be considered in genetic studies and clinical trials.

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.

Walking impairments in Parkinsons disease (PD), including reduced speed, cadence, and stride length, and increased variability, impair mobility and raise fall risk. Conventional treatments may fail to address these deficits, underscoring the need for complementary non-invasive alternatives. This study examined whether combining rhythmic auditory cueing with transcranial direct current stimulation (tDCS) over the supplementary motor area (SMA), a critical region for internally-generated movement, would enhance gait performance in PD. Thirty-three participants with PD and thirty-two healthy controls completed two sessions (anodal vs. sham tDCS) with gait assessed during stimulation, immediately after stimulation, and 15 minutes after stimulation under two auditory conditions: walking in silence and walking to music paced 10% faster than baseline cadence. Spatiotemporal, variability, and stability gait parameters were analyzed using linear mixed-effects models. Rhythmic auditory cueing significantly increased cadence and speed during, immediately after, and especially 15 minutes after stimulation, suggesting sustained effects of rhythmic entrainment. Anodal tDCS produced faster cadence, as well as lower stride time variability and stride width, particularly in individuals with PD. Although both music and anodal tDCS affected gait, no interaction was observed, indicating independent effects. Individuals with PD had greater gait variability overall, and adjusted temporal gait parameters less to music than healthy controls did. Anodal stimulation reduced walking variability in PD, reducing the group differences observed under sham conditions. These findings suggest that rhythmic cueing and SMA stimulation target complementary mechanisms, highlighting the promise of combined tDCS-music interventions for gait rehabilitation in PD.

Non-motor symptoms in Parkinsons disease (PD) may be influenced by the 4{beta}2* subtype of nicotinic acetylcholine receptors (nAChR) present in the hippocampus and subiculum. To continue efforts in PET diagnostics for PD, autoradiographic [18F]nifene binding to 4{beta}2* nAChR was quantitively assessed in the hippocampus-subiculum (HP-SUB) of PD (n = 27; 14 males, 13 females) and cognitively normal (CN) (n = 32; 16 males, 16 females) cases. Anti-ubiquitin for Lewy body and anti--synuclein immunostaining on adjacent slices were analyzed in QuPath and [18F]nifene binding was quantified in OptiQuant. Subiculum had greater [18F]nifene binding (51% to 85%) compared to HP in all subjects. Significantly higher [18F]nifene binding (>250%) was seen in PD SUB and PD HP compared to CN in both males and females. The grey matter (GM) to white matter (WM) ratio in PD=3.53 while CN=1.33, a >150% increase in PD. Binding of [18F]nifene to GM and WM individually was >250% greater in PD compared to CN. Male CN exhibited an increase while and male PD exhibited a significant decrease in [18F]nifene binding with aging, while females did not exhibit significant differences. In summary, 4{beta}2* nAChR measured by [18F]nifene is significantly upregulated in the PD HP and SUB. This increased [18F]nifene binding may be of diagnostic value using PET imaging.

IntroductionIntestinal constipation (IC) is a common and early non-motor symptom in Parkinsons disease (PD), impacting patients quality of life. In this context, the Mediterranean diet plays a fundamental role in managing IC. This study aimed to evaluate the effects of a nutritional education program based on the principles of the Mediterranean diet on IC in individuals with PD. MethodsThis is a randomized, controlled, single-center, parallel-group, single-blind clinical study to evaluate the effectiveness of a nutritional education program based on the Mediterranean diet for three months, with a delayed-start design, in people with PD and IC. Participants were randomly allocated (1:1 ratio) to two groups: early-start (intervention from baseline to the third month) and delayed-start (intervention from the third to the sixth month) nutritional counseling, with an initial in-person assessment and monthly remote assessments. Bowel habits, adherence to the Mediterranean diet, and clinical variables were analyzed. ResultsAfter six months, a significant increase in the frequency of weekly bowel movements was observed (Early-start: 2.91 to 4.14; Delayed-start: 2.68 to 4.18 bowel movements/week; p < 0.001), along with changes in stool consistency and improved adherence to the Mediterranean diet over time. However, no significant differences were detected between the groups. ConclusionA nutritional education program based on the principles of the Mediterranean diet was associated with improved bowel habits and dietary adherence over time. These results support that locally adapted, low-cost dietary counseling may represent a complementary approach to the treatment of IC in individuals with PD in non-Mediterranean settings.