npj Parkinson's Disease

Despite major progress in genomic risk loci identification, biological mechanisms underlying Parkinson's disease (PD) remain incompletely understood and the informativity of polygenic score (PGS)-based prediction remains modest. Polytranscriptomic scores (PTS) - the sum of an individual's observed gene expression weighted by transcriptome-wide association z-scores - combine the stability of genetics with the dynamic biology of gene expression and have the potential to identify associations not captured by genetics alone. We present the first large-scale cross-trait and multi-PTS analysis of PD, calculating ~550 PTS for 100 phenotypes using whole-blood RNA-seq data from three independent clinical cohorts in the Accelerating Medicines Partnership Parkinson's Disease programme (AMP-PD) (N = 2,741; NCASES = 1,644). We identify 26 Bonferroni significant cross-trait PTS associations with PD (p<9x10-5) involving 18 phenotypes and 11 trait categories, including neurodegenerative diseases, respiratory function, sleep and cardiovascular traits. Only one of these associations was observed using corresponding PGS, highlighting the added value of integrating directly measured transcriptomic data. Combining multiple PTS within machine learning multi-PTS models improved prediction of PD case/control status beyond age, sex and PD-PGS in external validation, with a sparse model including an additional seven PTS achieving an AUC of 0.74 [0.70-0.78], representing a 0.09-point improvement. These findings reveal transcriptomic overlap between PD and a range of clinically relevant traits, providing novel insights into disease biology with potential to improve disease prediction.

Background: Neurodegenerative diseases including Parkinson's disease (PD) are increasingly associated with dysfunction in both central and peripheral immune systems. Pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) represent a major cause of familial PD, while common polymorphisms are associated with inflammatory diseases. Methods: Here, using immunophenotyping flow cytometry and quantitative PCR (qPCR), we compared immune cell populations and function across both the central and peripheral immune systems in C57BL/6J wild type (WT), Lrrk2 p.G2019S knock-in (GKI) and Lrrk2 knock-out (LKO) models in basal and ex vivo immune-stimulated conditions. Results: With a focus on T cell biology, compared to their WT counterparts at baseline, GKI mice exhibit higher populations of Cd8+ and TH17 T cell subsets in the brain, whereas LKO mice exhibited unique central memory (TCM), follicular helper (TFH), and TH2 lineages. In the periphery, GKI mice demonstrated higher TH1, TH2, and TH17 subset expansions, whereas peripheral alterations in LKO are largely restricted to TH17 subsets. Within mutant genotypes, a striking discrepancy was observed between baseline gene expression and the translated proteins encoded, that reveals a fundamental loss of basal immune homeostasis. This phenomenon was further exposed following an acute (6-hour) ex vivo lipopolysaccharide (LPS) immune challenge. Following stimulation, GKI immune cells had reduced transcription, alongside stalled translation, for almost all effector molecules examined, while LKO immune cells had fewer transcriptional changes compared to wild type. Overall, both mutant lines had stalled or flatline effector molecule production after immune stimulation, suggesting a profound loss of functional responsiveness. This hypothesis was supported by a significant increase in surface protein of the inhibitory receptor Pd-1 on regulatory T cells (TREG) and TH1/TH2 Cd4+ T cell subsets in GKI mice. LKO immune landscapes trended toward similar exhaustion patterns, albeit less evident. Conclusions: These data suggest that bidirectional disruptions to normal Lrrk2 function break immune homeostasis. Immune cell function should be carefully considered when targeting LRRK2 kinase activity in patients with PD.

Parkinson disease (PD) affects more than 1.1 million individuals in the United States and around 12 million worldwide. Although Genome Wide Association Studies (GWAS) have substantially advanced our understanding of PD genetic architecture, the regulatory mechanisms linking PD risk loci to disease-relevant gene expression remain incompletely characterized, limiting our ability to infer disease mechanisms from genetic associations. Here, we integrated disease-state parietal cortex transcriptomics with the International Parkinsons Disease Genomics Consortium (iPDGC) locus prioritization to refine PD gene nomination and identify biologically plausible candidates missed by GWAS-only approaches. Using bulk RNA-seq from 99 neuropathologically confirmed PD cases and 30 neuropathologically confirmed controls, we prioritized candidate genes across 78 loci and classified them according to concordance between genetic evidence and differential expression in diseased cortices. This integrative approach recovered candidate genes not captured by external GWAS-based prioritization methods and highlighted synaptic, lysosomal, and proteostasis pathways as major components of PD risk biology. Network and transcription factor analyses further suggested coordinated regulation of these genes, with STAT3 emerging as a putative upstream glial regulator. Together, these findings suggest that integrating disease-state transcriptomics with genetic prioritization can refine PD risk-gene nomination and uncover regulatory programs that may be missed by GWAS alone.

Background An X-linked levodopa-responsive parkinsonism-epilepsy syndrome has been associated with PGK1, and the gene lies within the previously suspected PD locus PARK12. Objective To examine the association of common and rare PGK1 variants with PD. Methods We analyzed common and rare variants from Accelerated Medicines Partnership - Parkinsons Disease (AMP-PD) and UK Biobank (UKBB, total N=4,523 PD cases, 19,736 proxy cases, and 390,532 controls). To account for the X-linked location of PGK1, we used sex-stratified, combined regression models and optimized sequence Kernel association (SKAT-O) tests, followed by meta-analysis using MetaSKAT. Results We found no association between common or rare PGK1 variants and PD in sex-stratified or combined analyses, including after cross-cohort meta-analysis. Conclusion Although we did not find evidence supporting an association between PGK1 and PD, very rare pathogenic PGK1 variants may still contribute to syndromic parkinsonism. Future research could explore larger datasets to further examine this potential association.

Parkinsons disease (PD) affects an estimated 6.4 million men and 5.3 million women worldwide, and still lacks a validated peripheral biomarker. Brain tissue is inaccessible in living patients, making peripheral blood an attractive alternative, but existing studies have profiled immune cells almost exclusively as static, resting-state snapshots that cannot reveal how those cells function under challenge. A longitudinal design, following patients over time, or applying a controlled stimulus to reveal functional differences invisible at rest, offers a more sensitive window onto disease-associated dysfunction, and sex, despite differential PD incidence and progression, is rarely treated as a primary variable. Here, using ex vivo PMA/ionomycin stimulation as a controlled functional challenge, we profiled 195k PBMCs from 84 samples of 14 PD patients and 14 controls by single-cell RNA sequencing across an activation time course (0h, 2h, 4h), stratified by sex throughout. Sex explained more transcriptional variance than disease status, and male and female PD patients showed largely divergent responses at rest that converged, by peak activation, on a discrete CD8+ effector memory T cell subpopulation (Tem-CD8). This subpopulation showed an exhaustion-consistent programme, coinciding with a failure to resolve AP-1 induction and a reduction in inferred intercellular communication. The PD peripheral immune phenotype is therefore better characterised as a activation-dependent response than a fixed resting-state signature, identifying Tem-CD8 exhaustion as a disease-associated, sex-convergent candidate for further study.

Dopamine replacement therapy (DRT) alleviates motor symptoms in Parkinson's disease (PD) but can trigger hallucinations in a subset of patients, yet the neural basis of this selective vulnerability is unknown. Hallucinations are among the most disabling non-motor symptoms of PD, linked to social isolation, dementia and institutionalization. Using a validated robotic paradigm to induce and quantify hallucinations in real-time, combined with resting-state fMRI in a crossover On/Off DRT design, we studied patients with PD with (PD-H) and without (PD-nH) hallucinations. DRT selectively amplified sensitivity to robot-induced hallucinations in patients with pre-existing hallucinatory phenotype (PD-H, but not PD-nH) and was accompanied by cortico-striatal and large-scale network hyperconnectivity. Rather than supporting a uniform hallucinogenic effect of dopamine in PD, these findings indicate that DRT interacts with an intrinsic neural vulnerability that varies in patients. Prospective studies will establish whether this pharmacological-behavioural signature identifies patients at risk before clinical hallucinations emerge.

Objective and scalable approaches for detecting subtle motor impairment in isolated REM sleep behavior disorder (iRBD), a prodromal stage of Parkinson's disease, remain limited. We investigated whether markerless motion capture from single RGB-camera videos can identify gait abnormalities in people living with iRBD and provide interpretable digital biomarkers. We retrospectively analyzed 93 standardized walking videos from three clinical sites. Human pose estimation extracted 12 body markers and 14 kinematic time series. Thirty-five machine learning approaches classified healthy controls (HC) and people with iRBD. The Movement Disorder Society Unified Parkinson's Disease Rating Scale Part 3 (MDS-UPDRS III) served as the clinical baseline. The best-performing model (tsfresh+XGBoost) achieved an AUROC of 0.739, significantly outperforming the MDS-UPDRS III sum score when trained on data from all three sites. Harmonized multi-site training improved performance. SHAP identified hip-related temporal features as key contributors, which differed between groups and showed stronger associations with regional dopaminergic deficits than clinical scores. Single-camera gait analysis may provide scalable digital biomarkers for low-cost screening and monitoring of prodromal PD.

Parkinsons disease (PD) is the second most common neurodegenerative disorder worldwide, and mutations in the LRRK2 and PRKN genes are among the most common familial causes of the disease. In neurodegenerative diseases such as PD, disturbances in Ca{superscript 2} homeostasis and cellular bioenergetics impair the function of neurons and glial cells, contributing to disease progression. These changes are not limited to neurons; mitochondrial dysfunction and disrupted Ca2+ homeostasis in astrocytes are increasingly recognized as key contributors to PD, impairing bioenergetics, redox balance, neuroinflammatory responses, and metabolic support essential for dopaminergic neuron survival. In this study, we investigated mitochondrial calcium homeostasis, mitochondrial oxidative phosphorylation, morphology and distribution in human induced pluripotent stem cell (hiPSC)-derived astrocytes with mutations in the PD genes LRRK2 (G2019S) and PRKN (c.155delA; Ex3-4del) and wild-type controls. Intracellular calcium dynamics were assessed using Fura-2 AM. Compared with control astrocytes, LRRK2-related PD patient-derived mutant astrocytes exhibited lower intracellular calcium levels, and slower calcium extrusion following stimulation with ATP. Mitochondrial morphology was analyzed using MitoTracker Deep Red, revealing increased mitochondrial fragmentation and redistribution of mitochondria toward the cell periphery in both PD mutant cell types. Because oxidative phosphorylation is tightly regulated by mitochondrial morphology and calcium homeostasis, we next assessed oxygen consumption rates using a continuous metabolic monitoring system (Resipher) and quantified the expression of genes (RT-qPCR) and proteins (capillary electrophoresis-based western detection) involved in mitochondrial calcium transport and bioenergetics. These analyses showed that PRKN mutant astrocytes exhibit a more oxidative bioenergetic phenotype than LRRK2 mutant astrocytes, while both mutant lines displayed altered phosphorylation of mitochondrial morphology regulator DRP1 as well as decreased levels of respiratory complexes relative to control astrocytes. In summary, this study identifies astrocyte-specific mitochondrial dysfunctions and calcium dysregulation as key features of LRRK2- and PRKN-related pathology, providing new insights into how glial metabolic alterations contribute to neurodegeneration in PD.

Isolated REM sleep behaviour disorder (RBD) is the strongest prodromal marker of Parkinson's disease (PD) and dementia with Lewy bodies, yet diagnosis requires video-polysomnography with assisted montage and expert scoring and does not scale to screening or trial enrichment. We developed a fully automated, self-applied system that detects RBD from a pair of electrodes placed behind the ears, with no manual scoring at any stage. A novel bipolar mastoid ExG derivation enables both sleep staging and quantification of REM sleep without atonia (RWA). A fine-tuned deep-learning 1-channel model staged sleep at a Cohen's kappa of 0.65 in PD, iRBD and controls ({kappa} = 0.73 for the 2-channel model). Automated mastoid RWA correlated strongly with expert chin SINBAR scoring (r = 0.82). In self-applied home recordings from 76 participants, the 1-channel system detected RBD with an AUC of 0.95 (sensitivity 94%, specificity 86%), reproduced on in-lab polysomnographies (AUC 0.93, n = 378). In RBD, between-night RWA variability warrants repeated nights for prognostic monitoring. The system provides a scalable tool for RBD detection and a continuous RWA measure for longitudinal studies of neurodegeneration.

The Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is the global standard for characterising Parkinson's Disease (PD) in clinical contexts. However, the specific symptom phenotypes it captures remain poorly understood, potentially limiting its value for diagnosis, prognosis, and stratifying patients. To address this, we developed a spectral estimation approach to find the unique latent variables captured by the 60 scores of MDS-UPDRS parts I, II, and III from 852 sporadic PD patients. Our analysis revealed six latent variables that robustly captured variation between patients and generalised across cohorts. The primary variable encoded symptom laterality, while others encoded distinct clinical features including tremor severity, and revealed an unexpected dissociation between patient self-reported symptoms and clinician-assessed symptoms, highlighting potential gaps in how PD is currently evaluated and understood. Our findings open the door to precise MDS-UPDRS phenotyping of patients for treatments and clinical trials.

Dopaminergic neurons in the substantia nigra pars compacta are key targets of -synuclein pathology and neurodegeneration in Parkinson's disease (PD). It is thought that pathological accumulation of -synuclein significantly contributes to nigral neuronal dysfunction and ensuing neuronal demise. In this study, we further assessed this possibility and interrogated the role of -synuclein burden in compromising neuronal function and altering physiological neuronal pathways. In particular, we focused on nigral mitochondrial impairment and disruption of circadian regulatory pathways triggered by sustained -synuclein expression. Using an in vivo AAV-mediated model, we show that -synuclein accumulation over a period of 12 weeks is associated with mitochondrial complex I and IV deficits and leads to dopaminergic cell loss. Proximity ligation assays revealed association of both total and phosphorylated -synuclein with mitochondrial proteins at a time (between 4 and 12 weeks) that paralleled the development of mitochondrial dysfunction. Spatial transcriptomic analysis of the substantia nigra identified coordinated alterations in genes involved in mitochondrial, metabolic, and circadian pathways, including increased expression of circadian-associated genes such as Nr1d1, Nr1d2, Cry2, Arntl2, and Csnk1e. At the protein level, -synuclein overexpression was associated with a differential shift in cryptochrome protein expression, characterized by reduced CRY1 and increased CRY2. Data provide evidence of a specific window of time during which sustained -synuclein burden results in direct -synuclein-mitochondria interactions and nigral mitochondrial damage. During the same time period, a specific remodeling of molecular clock components occurs, providing a potential new mechanism contributing to metabolic and mitochondrial dysregulations and, ultimately, neuronal injury and degeneration.

The genetics of Parkinsons disease (PD) in underrepresented populations remain poorly characterized, potentially overlooking population-specific contributions. We analyzed 461 Chilean PD cases from a movement disorders center. Pathogenic, likely pathogenic, or GBA1 risk variants were identified in 58 individuals (12.6%), mainly in LRRK2 (50%) and GBA1 (44.8%), while PRKN, SNCA, and SQSTM1 collectively represented 5.2%. All LRRK2 variants were p.G2019S, with an overall frequency of 6.3%, the highest reported in South America, and enrichment of Ashkenazi Jewish ancestry at this locus. These findings characterize the genetic landscape of PD in Chile and support its relevance for LRRK2-targeted studies.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for Parkinson's Disease (PD), but identifying optimal stimulation contacts is time-intensive. Beta-band activity (13-35 Hz) from local field potentials (LFP) correlates with motor symptoms and attenuation by dopaminergic therapy and DBS supports its role as a programming biomarker. The recently introduced Electrode Identifier (EI) feature of Medtronic PerceptTM neurostimulators may facilitate beta-guided contact selection. Objective: To evaluate whether pseudo-monopolar STN beta power obtained using EI predicts optimal stimulation contacts and compare its performance with reconstructed bipolar recordings and MPR. Methods: LFPs were recorded in 69 patients using EI and Electrode Survey (ES). Prediction accuracy was assessed using predefined ranking rules and compared with clinically selected contacts. Agreement between EI, ES, and MPR was evaluated. Motor outcome was assessed using MDS-UPDRS-III. Results: EI predicted clinically selected contacts above chance (TOP1: 45%, p = 0.010; TOP2-80: 57%, p = <0.001), whereas ES exceeded chance only under more inclusive selection criteria (TOP1: 38%, p = 0.073; TOP2-80: 55%, p = 0.0021). Accuracy did not differ between methods (TOP1: p = 0.720; TOP2-80: p = 1.000). EI showed highest agreement with MPR and tended to select ventral contacts. Neither method predicted motor outcome, although EI-matched contacts showed a trend toward greater improvement. Due to technical constraints, one-third of EI recordings were excluded. Conclusions: Pseudo-monopolar STN beta power provides clinically relevant information for DBS contact selection with performance comparable to bipolar approaches. Further improvements are needed before clinical implementation.

Parkinson disease (PD) is characterized by excessive neural synchronization in the 13 to 30 Hz beta band within basal ganglia circuits. Conventional therapies, including dopaminergic medication and deep brain stimulation (DBS), reduce beta synchrony while enhancing lower-frequency theta activity. As an adjunct to these treatments, music and auditory rhythms improve motor function in PD, but the neural mechanisms remain unclear. Here, we recorded local field potentials in the subthalamic nucleus (STN) of patients with PD in the medication off state to test how structured musical elements shape subcortical synchrony. Spectral and neural state-space analyses showed that rhythmic and harmonic components of music produced effects comparable to dopaminergic therapy, suppressing beta-band oscillations while enhancing theta band activity. These effects were strong in the dorsal sensorimotor STN, whereas the ventral limbic STN showed minor modulation. Directional connectivity analysis further revealed that music-induced beta and theta changes were accompanied by increased cortex to STN drive, consistent with top down recruitment of the cortical subthalamic hyperdirect pathway. Notably, harmonic consonance produced network-level modulation comparable to, and in some cases greater than, rhythmic entrainment, extending beyond the established framework of beat based basal ganglia engagement. Together, these findings identify frequency selective, region specific, and stimulus-locked mechanisms by which music reshapes pathological basal ganglia activity in PD, providing direct electrophysiological evidence that auditory stimulation can transiently shift subcortical dynamics toward a medication like state.

BackgroundFreezing of gait (FOG) in Parkinsons disease is associated with abnormal beta activity in the subthalamic nucleus (STN), but the temporal structure of burst dynamics remains poorly understood. ObjectivesTo determine whether temporal features of STN beta bursts distinguish pre-freeze from stable gait and predict freezing onset. MethodsSTN recordings during gait from four individuals were analyzed. Temporal features of burst timing, including entropy and variability, were computed across behavioral states. Predictive performance was assessed using leave-one-patient-out classifiers. ResultsEntropy of inter-burst intervals was reduced prior to freezing (p < 0.01), with strong predictive performance (AUC = 0.825; threshold AUC = 0.858). During freezing, variability measures decreased and temporal structure increased, while entropy did not differ from pre-freeze. Phase-amplitude coupling showed frequency-specific but heterogeneous effects across comparisons. ConclusionsReduced temporal variability of STN beta burst timing precedes and predicts freezing, suggesting a transition to constrained neural dynamics.

Blood-based (BB) biomarker investigations in Parkinson disease (PD) and in mild traumatic brain injury (mTBI) have substantially grown over the past decade. High risks for PD in young post-mTBI veterans have been inferred from medical record data using actuarial modeling. However, potential utility of BB biomarkers to quantify risks vs. no risk for PD in young post-mTBI veterans has not been established. Previously we reported post-mTBI veterans performed significantly below the standardized normative scores for their age and education level on specific domains of executive functioning, on par with senior aged individuals with early-stage PD. Here, we examined serum brain-derived neurotropic factor (BDNF), ubiquitin C-terminal hydrolase-L1 (UCH-L1), glial fibrillary acidic protein (GFAP), and S100 calcium-binding protein {beta} (S100B) in association with executive functioning outcomes in search of a bio-cognitive model suitable to differentiate risk from no risk for prodromal PD. A reference range of bio-cognitive cut-points were derived from Area Under the Curve (AUC) sensitivity and specificity methods. Our data revealed two bio-cognitive signatures with reference range cut-points when GFAP was paired with cognitive flexibility / attention scores, and when S100B was paired with categorical / semantic verbal memory scores. Both bio-cognitive signatures revealed prodromal PD risk vs.no-risk parameters that remained relevant for differentiating young veterans who had encountered a past mTBI and those who had not experienced a mTBI. Subjects with early-stage PD who had withstood a mTBI up to 10- to 40-years earlier were also differentiated from those who had no mTBI history. These results indicate the predictive utility of expanding the biomarker field to include reference ranges, cut-points, and specific cognitive domains to estimate risks for PD in a clinic setting. These preliminary data also add value in establishing a quantifiable bio-cognitive risk signature to identify prodromal PD risks in young adults prior to obvious cognitive and motor decline. While encouraging, these data require further follow-up with a larger sample size in a longitudinal design to validate these findings.

Background: People with Parkinsons disease (PD) experience substantial psychosocial burden, but the extent of their concern about the future is not well characterized. Objective: The objective of the present study is to characterize concerns about the future among people with PD (PwP), with an emphasis on the clinical and demographic correlates of future-oriented concerns. Methods: A survey in the online Fox Insight study platform asked PwP to rate their degree of concern about the future across seven domains: quality of life, disease progression, healthcare needs, social relationships, financial responsibilities, stigma, and specific symptoms. Relationships among uncertainty and demographic and clinical features, such as age of onset, gender, and disease severity, were examined. Latent class analysis was conducted to identify patterns of fear/uncertainty. Results: Among 3372 respondents, concerns about the future were common and spanned cognitive, functional, social, and symptom-related domains. Concerns about future cognitive impairment, independence, mobility, and disease progression were most prominent. Women and individuals with young-onset PD reported higher levels of concern than other groups. Latent class analysis revealed two clear patterns, including a high-concern subgroup with elevated worry across nearly all domains. Fewer than half of respondents had discussed these concerns with a healthcare professional. Conclusion: Future-related concerns are common among people with PD but is not routinely explored in clinical care. Greater attention to these concerns, especially for young-onset individuals and women, may help clinicians offer more timely and supportive guidance.

Background: Levodopa is time-critical in hospitalized Parkinson disease. Whether dosing fidelity depends on care setting or documented access status is unclear. Objectives: To quantify levodopa dosing fidelity, test ICU exposure with clustering-aware methods, and test whether documented access type is associated with delayed or omitted dosing. Methods: Retrospective cohort study using MIMIC-IV (2011-2022). Adults with Parkinson disease and [&ge;]1 scheduled levodopa dose contributed 1,665 admissions and 39,322 doses. ICU exposure was tested with a patient-clustered GEE model. Among ICU-exposed doses, access type (normal, tube feeding, parenteral nutrition, NPO) was modeled in one fully adjusted model and tested for specificity, restricted to the ICU, against an active-comparator medication (statins). Results: Of 39,322 doses, 79.8% were on time by the primary 60-minute definition; a symmetric {+/-}15-minute definition classified 68.8% as mistimed. ICU exposure was not associated with delayed or omitted dosing after clustering (patient-clustered OR, 0.87; 95% CI, 0.74-1.01). Among ICU-exposed doses, NPO was associated with delayed or omitted dosing (adjusted OR, 1.89; 95% CI, 1.36-2.62) and tube feeding with lower odds (adjusted OR, 0.62; 95% CI, 0.42-0.92; P < .001). The comparator medication showed a directionally consistent but inconclusive interaction (OR, 1.27-1.28; 92 patients). A route-order association was not observed among immediate-release formulations (OR, 0.72; 4 patients). Conclusions: ICU admission alone was not associated with dosing unreliability after clustering. Among ICU-exposed doses, access type, not a single pooled category, was associated with dosing reliability; a comparator-medication check, valid only in the ICU, was directionally consistent but inconclusive.

Transcranial alternating current stimulation (tACS) is a promising noninvasive intervention for modulating pathological brain oscillations in Parkinson's disease (PD). To evaluate its clinical and neurophysiological efficacy, we searched five databases (Web of Science, PubMed, Scopus, Google Scholar and APA PsycInfo) up to August 31, 2025, for trials employing tACS in patients with idiopathic PD. Risk of bias was assessed using the RoB 2 and ROBINS-I tools. Random-effects meta-analyses were used to calculate standardized (SMD) and unstandardized mean differences (MD) with 95% confidence intervals (CIs). We included 10 studies (184 patients with PD, mean age: 64.9, mean disease duration: 5.2 years) in the qualitative review and seven trials (146 patients with PD, mean age: 65.6, mean disease duration: 5 years) in the meta-analysis. No statistically significant differences favoring active tACS over control were found in overall motor severity (UPDRS: SMD = 0.21, 95% CI [-0.10, 0.52], p = 0.097), tremor (SMD = -0.40, 95% CI [-1.97, 1.17], p = 0.478), or a neurophysiological marker of inhibitory response, represented by short intracortical inhibition (MD = 0.00, 95% CI [-0.40, 0.41], p = 0.971). The prediction intervals indicated substantial uncertainty, and significant between-study heterogeneity was observed, particularly for tremor outcomes (I2 = 86.1%). This variability and limitation in evidence quality is largely driven by small sample sizes, highly heterogeneous stimulation protocols, and varying outcome assessments. Systematically, tACS was generally well-tolerated, with no serious adverse events reported across the included studies; however, formal safety assessment was beyond the scope of this review. Current exploratory evidence shows a lack of consistent improvements in motor symptoms or functions in PD largely due to protocol-level heterogeneity. Future studies should consistently assess the MDS-UPDRS III post-tACS and report its specific subscores alongside neurophysiological measures to enable robust meta-analyses.

Parkinson's disease (PD) is characterized by progressive DAergic neurodegeneration and the accumulation of aggregated -Synuclein (Syn), which drives chronic neuroinflammation through sustained activation of innate and adaptive immune responses. Regulatory T cells (Tregs) exert potent immunosuppressive functions and have shown neuroprotective effects in preclinical PD models; however, clinical translation of polyclonal Treg therapies has been limited by poor tissue specificity and insufficient therapeutic efficacy. To overcome these limitations, we engineered induced human Tregs (iTregs) expressing chimeric antigen receptors (CARs) directed against pathological Syn aggregates. Among the CAR designs tested, only a nanobody-based construct incorporating NbSyn87 displayed selective antigen-dependent activation in response to Syn preformed fibrils (PFFs). Intriguingly, despite the ability of the parental NbSyn87 nanobody to bind both monomeric and aggregated Syn, incorporation into the CAR architecture conferred functional selectivity for aggregated conformers. This feature enabled discrimination between pathological extracellular aggregates and physiological monomeric Syn, providing an important safety advantage. To evaluate therapeutic activity in vivo, we established an immunodeficient mouse model of synucleinopathy permissive to human cell engraftment. iTregs preferentially accumulated within Syn-rich brain regions and, in the presence of astrocyte-derived human IL-2 with antigen-independent mechanism. Conversely, only CAR iTregs directed against Syn significantly reduced microglial and astrocytic activation, decreased pro-inflammatory cytokine expression, and attenuated Syn pathology. Collectively, these findings demonstrate that Syn-specific CAR iTregs can selectively exert potent local immunomodulatory effects, establishing a promising antigen-specific cellular immunotherapy platform for PD and other synucleinopathies.