The genetic architecture of Parkinson's disease varies considerably across ancestries, yet most previous genetic studies have focused on individuals of European ancestry. We aimed to characterise the distribution of established Parkinson's disease causal variants, as well as risk-associated variants with clinical implications (ie, variants in genes involved in pathways targeted by ongoing clinical trials), across ancestrally diverse populations. We conducted a multi-ancestry, observational, cross-sectional genetic study using retrospective data from the Global Parkinson's Genetics Program (GP2) release 11 (released in December, 2025). The study investigated causal and risk variants, including copy number variants, in established Parkinson's disease and parkinsonism-associated genes, following the recommendations of the Movement Disorder Society (MDS) Task Force on the Nomenclature of Genetic Movement Disorders, including GBA1, LRRK2, SNCA, VPS35, RAB32, PINK1, PRKN, PARK7, ATP13A2, DCTN1, DNAJC6, FBXO7, JAM2, RAB39B, SLC20A2, SYNJ1, VPS13C, and WDR45. Individuals with Parkinson's disease were diagnosed based on established clinical criteria, including the Parkinson's UK Brain Bank or MDS diagnostic criteria (or both), and healthy control participants were defined as individuals without evidence of neurodegenerative disease and unrelated to participants with Parkinson's disease. We analysed genome and exome sequencing and array genotyping data of 99 783 individuals, including 58 559 individuals with Parkinson's disease and 41 224 controls, from 11 genetically inferred ancestries (African, African admixed, Ashkenazi Jewish, Latino and Indigenous people of the Americas, central Asian, complex admixture, east Asian, European, Finnish, Middle Eastern, and south Asian), defined using reference population-based ancestry inference methods. We calculated allele frequencies for all investigated variants in individuals with Parkinson's disease and controls, both overall and stratified by ancestry. Approximately 29% of individuals (29 001 of 99 783; 15 443 [26·4%] of 58 559 individuals with Parkinson's disease and 13 558 [32·9%] of 41 224 controls) were from under-represented populations (ie, non-European and non-Ashkenazi Jewish). Our findings indicated both shared genetic contributors across ancestries as well as ancestry-specific differences in variant frequencies and the spectrum of variants within Parkinson's disease-associated genes. Overall, 1217 (2·1%) of 58 559 individuals with Parkinson's disease carried a causal variant, with substantial variations across ancestries ranging from ten (0·4%) of 2844 African individuals to 251 (10·7%) of 2343 individuals of Ashkenazi Jewish ancestry. Risk variants in GBA1 and LRRK2 were identified in 6893 (11·8%) of 58 559 individuals with Parkinson's disease and 3578 (8·7%) of 41 224 controls. GBA1 risk variants were most frequent overall and identified across all ancestries, but variant frequency and spectra differed substantially between ancestries, from 195 (4·1%) of 4773 in the east Asian ancestry group to 1505 (52·9%) of 2844 in the African ancestry group. Similarly, LRRK2 causal and risk variants showed ancestry-specific enrichment, with the highest frequencies of causal variants in the Ashkenazi Jewish (250 [10·7%] of 2343) and Middle Eastern (59 [4·4%] of 1347) ancestry groups, whereas risk variants were predominantly identified in the east Asian ancestry group (601 [12·6%] of 4773). Carriers of biallelic causal variants in PRKN, commonly including deletions and duplications, were also identified across all ancestries except Ashkenazi Jewish; the highest frequency was in the Middle Eastern ancestry group (17 [1·3%] of 1347), and frequencies in all other ancestries were less than 1%. This large-scale, multi-ancestry genetic study offers crucial insights into the population-specific genetic architecture of Parkinson's disease. Whereas clinical trials targeting GBA1 and LRRK2 variant carriers are primarily performed in Europe and the USA, increased ancestral diversity in Parkinson's disease research will be crucial to improve diagnostic accuracy, enhance our understanding of disease mechanisms across populations, and ensure equitable application of and access to emerging genetically informed therapies. Aligning Science Across Parkinson's (ASAP) through the Global Parkinson's Genetics Program (GP2).
Disruption of circadian rhythms is a key feature of neurodegenerative diseases and a non-motor feature of Parkinson's disease, which significantly impairs health-related quality of life; yet, the underlying mechanisms are only partially understood. Preclinical animal models with neuropathological and symptomatic significance might contribute to a better understanding of circadian dysfunction. Here, we investigated light-dark phase-dependent modulation of motor and non-motor behavior as well as suprachiasmatic nucleus integrity in α-synuclein-overexpressing rats and wild-type controls. Behavioral testing in 3-month-old animals revealed robust phase-dependent modulation of exploratory activity, locomotion, sucrose preference, and olfaction-guided feeding in wild-type rats, which was absent in their transgenic littermates. Histological analyses demonstrated reduced overall cell density and pronounced α-synuclein accumulation in the suprachiasmatic nucleus of α-synuclein rats, accompanied by altered cellular composition, including altered neuronal, orexinergic, and microglial markers. α-synuclein load was positively correlated with Orexin A+ fibers and Iba1+ cell counts, suggesting a link between protein aggregation, neuroinflammation, and altered light-dark phase-dependent behavior. These findings indicate that α-synuclein rats lack phase-dependent behavioral alternations and exhibit suprachiasmatic nucleus pathology already at an early disease stage with very mild motor impairment, providing a translational model to study different aspects of non-motor symptoms in Parkinson's disease.
Parkinson's disease (PD) heterogeneity complicates disease-modification clinical trial design and lead to ambiguous results, necessitating robust subtyping frameworks to identify rapid progressors. This study compared progression milestones across previously defined clinical (tremor-dominant [TD], postural instability/gait difficulty [PIGD], indeterminate), pathological (brain-first, body-first), and data-driven (diffuse malignant [DM], intermediate [IM], mild motor-predominant [MMP]) PD subtypes. Using data from the Parkinson's Progression Markers Initiative (PPMI), we analyzed milestone attainment across six functional domains and performed Cox proportional hazards regression. Randomized controlled trial sample size simulations evaluated the impact of subtyping on trial efficiency. Data-driven subtypes exhibited the highest progression rates, with DM patients attaining 63.0% of milestones, surpassing PIGD (55.6%) and body-first (54.0%) subtypes. Cox proportional hazards regression confirmed that DM patients had the highest hazard of progression compared to MMP, after adjusting for age at enrollment. Trial power simulations demonstrated that enrolling DM patients could reduce sample size requirements by approximately 50% using standard trial durations compared to unstratified PD cohorts. This analysis showed that data-driven subtyping, particularly the identification of the DM subtype, offers a promising strategy to optimize disease-modification trials in PD by capturing patients who meet progression milestones earlier.
Variation at the 17q21.31 locus, which contains the gene encoding microtubule-associated protein tau (MAPT), has been associated with neurodegenerative disorders, including Parkinson's disease (PD). This highly complex locus is characterized by two broadly defined haplotypes: H1 and the inverted H2 haplotype. While H1 has been associated with an increased PD risk and is present in all ancestry populations, H2 is enriched in individuals of European ancestry. So far, few studies have explored the H1 association with PD in non-European ancestries. Here, we investigated the haplotype and subhaplotype frequencies of H1 and H2 in 20,507 PD patients and 11,841 controls across eleven different ancestry groups from the Global Parkinson's Genetics Program (GP2) and the Latin American Research consortium on the GEnetics of Parkinson's Disease (LARGE-PD). Our results strongly support the involvement of the H1 haplotype in PD risk in individuals of European ancestry, with additional evidence suggesting an association across diverse ancestry groups. Additionally, we observed significant variation in the H1 subhaplotype frequencies within populations, highlighting the complexity of this genomic region and the relevance of its study in diverse ancestries to gain a more comprehensive understanding of the role this locus plays in neurodegenerative disease risk.
LRRK2 (leucine-rich repeat kinase 2) and Parkin (PRKN) act in shared pathways and are implicated in Parkinson's disease (PD), leprosy, and other diseases. While leprosy likely imposed strong evolutionary pressure, PD's relatively late onset renders it largely invisible to natural selection. We examined the evolutionary history of LRRK2 and PRKN in primates and human populations and found evidence of positive selection on both genes, alongside strong constraint at LRRK2 disease-associated sites. Gibbons were found to carry a pathogenic PRKN mutation (R33Q) causing protein instability. Using ancient DNA, we traced the dynamics of LRRK2 and PRKN variants in Europe and showed that the common PD risk allele LRRK2 G2019S-also protective against salmonellosis-was absent in Paleolithic populations but rose rapidly during the Early Neolithic, likely driven by selection from emerging human-adapted Salmonella. Four leprosy susceptibility variants in PRKN and other loci increased in frequency before the Middle Ages, with little evidence of strong selection during the medieval epidemic itself. Together, these results link a major PD mutation to ancient infectious pressures and suggest that pathogen-driven selection shaped leprosy susceptibility in Europe prior to its medieval peak.
Impaired clearance of pathogenic proteins may contribute to Parkinson's disease (PD) progression, but the clinical relevance of brain clearance-associated processes in humans remains incompletely understood. Using cross-sectional data from 1,861 participants (704 PD, 997 prodromal, 160 healthy controls) in Parkinson Progression Marker Initiative, we investigated whether the magnetic resonance imaging (MRI)-based indirect markers linked to brain clearance-related processes, diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index and normalized choroid plexus volume (NCPV), are associated with disease stage and motor/non-motor manifestations across the PD spectrum. The ALPS index declined with age, was lower in males, and showed a stepwise reduction from controls to prodromal individuals and PD patients. Clinically, lower ALPS index correlated with greater motor severity in prodromal and PD groups, with stronger associations at advanced stages. Lower ALPS index also correlated with rapid eye movement sleep behavior disorder, cognitive impairment, and depressive symptoms. NCPV showed a complementary trend, demonstrating positive associations with clinical severity measures and a significant negative correlation with the ALPS index. Together, these findings suggest that MRI markers linked to brain clearance processes are associated with clinical progression across the PD continuum and may provide imaging biomarkers relevant to disease staging and pathophysiology.
Circadian disruption and metabolic stress are implicated in Parkinson's disease (PD), but the epigenetic mechanisms linking nutrient fluctuations to circadian regulation remain poorly understood. Here, we combined genome-wide 5-hydroxymethylcytosine (5hmC) profiling, CRISPR-based genetic perturbations, and circadian models to investigate how glucose availability shapes epigenetic dynamics and circadian transcription. We found that low glucose activates AMP-activated protein kinase (AMPK), upregulating TET2 transcription and increasing global 5hmC remodeling. These effects are reversible upon glucose restoration and are abolished by AMPK deficiency, establishing AMPK as a key mediator of metabolic control over TET2. Notably, Tet2 exhibits intrinsic circadian rhythmicity and is temporally coupled with clock-associated gene expression. Disruption of TET2 impairs glucose-responsive 5hmC dynamics and alters circadian transcriptional outputs. Together, our findings define a glucose-responsive AMPK-TET2-5hmC axis that links metabolic state to epigenetic and circadian regulation. This work provides a mechanistic framework for understanding how metabolic dysfunction may contribute to circadian abnormalities in Parkinson's disease.
Growing evidence suggests that a part of the burden of Parkinson's disease (PD) can be explained by exposure to environmental factors, including pesticides, heavy metals, solvents, and air pollution. However, several questions remain unanswered, pertaining to the associations with PD of environmental factors that are still in use today; the added risks of co-exposure to multiple environmental factors and gene-environment interactions. Additional questions remain on the relevant time window, duration, and level of environmental exposures in relation to PD risk. Furthermore, it is unclear whether these exposures are associated with clinical progression of PD. PD-PEST (Parkinson's Disease-Preventing Emergence of Symptoms by environmental Toxicants) is a nationwide hospital-based case-control study conducted in the Netherlands. The study population consists of 1500 persons with a recent PD diagnosis and 3000 age- and sex-matched controls. Participants will be recruited from four regions across the Netherlands to ensure a representative geographical distribution in terms of urbanisation, industry, and agricultural activity. Cases must have a PD diagnosis, established by a neurologist in the Netherlands according to standard diagnostic criteria. Controls are outpatients with a different neurological condition that is unlikely to be associated with the environmental factors of interest or the risk of PD. We will collect detailed information on historical and current environmental exposures at an individual level. This includes occupational and residential histories (via questionnaires and nationwide registries) and measurements (blood, saliva, faeces, hair, and via silicone wristbands). Based on these multimodal data, we will estimate participants' individual lifetime exposure to environmental factors. Then, we will examine the associations between these exposures and the risk of PD. In addition, we will assess longitudinal associations between exposures and clinical progression of individuals with PD over 36 months. Analyses will be adjusted for possible confounders and multiple hypothesis testing. The PD-PEST study aims to overcome the limitations of previous studies by examining a large, representative study population, incorporating detailed information on clinical PD diagnosis, conducting extensive assessments of historical and current environmental risk factors and collecting detailed information on possible confounders. The results are expected to enhance our understanding of the role of environmental factors in the aetiology of PD and inform preventive strategies. The Medical Ethical Committee Oost-Nederland approved this study (NL86526.091.24). Informed consent will be obtained from each participant prior to participation in any of the study procedures. Findings of this study will be disseminated through publications, conferences, stakeholder briefings, and tailored communication materials for participants and the wider Parkinson community. Open Science Framework, January 2025 (osf.io/4q9vs).
Dopaminergic degeneration in Parkinson's disease disrupts large-scale brain networks, yet how dopamine loss and its treatment shape the brain's dynamic reconfiguration over time remains unknown. We combined resting-state fMRI with dopamine transporter scan in 136 drug-naive patients and 20 healthy controls from the PPMI cohort to determine how dopamine transporter availability relates to dynamic network reconfiguration, indexed by how brain regions switch communities over time. Patients showed reduced modular reconfiguration in the default-mode network. Dopamine transporter availability was differentially associated with reconfiguration, showing negative associations in visual and positive associations in limbic networks. Cognitive performance correlated with attention network reconfiguration, whereas motor impairment tracked dopamine loss. Longitudinal analyses in a subset with one year follow-up (n = 29) showed that network reconfiguration increased with dopaminergic decline, and medication modulated these dynamics toward the pattern seen in healthy controls. Our findings demonstrate that network reconfiguration captures dopamine-sensitive and cognition-relevant alterations in early Parkinson's disease.
Expanded short tandem repeats contribute to a broad spectrum of neurodegenerative diseases, yet their roles in Parkinson's disease (PD) and parkinsonism remain incompletely characterized, especially across diverse ancestries. We analyzed short-read whole-genome (WGS) and clinical exome sequencing (CES) data from 38,365 individuals (28,861 WGS; 9,504 CES), encompassing 23,242 patients with PD, 4,729 patients with atypical parkinsonism and 10,394 healthy controls from 11 genetic ancestries. To determine carrier frequencies and characterize repeat structures across diverse ancestries, we genotyped 12 established pathogenic loci where normal, intermediate, and pathogenic alleles can be reliably differentiated using short-read sequencing data. Additionally, we conducted threshold-based associations to determine the minimum threshold associated with increased PD risk in 15,995 individuals (8,591 PD, 7,404 controls) of European ancestry. Pathogenic repeat expansions were detected in 62 patients (56 PD and 6 atypical parkinsonism) and 5 controls across seven loci (AR, ATXN1, ATXN2, ATXN3, CACNA1A, HTT and THAP11), spanning seven ancestries. Among these, ATXN2 expansions were the most frequently observed in PD and were present in African, East Asian, European and Middle Eastern ancestries. Additionally, intermediate ATXN2 repeat expansions exhibited a strong, length-dependent association with PD risk in the European population, with individuals with ≥32 repeats having a more than four-fold increased risk (odds ratio 4.25, 95% confidence interval 1.80-12.05). Overall, >92% of expanded alleles harbor CAA interruptions within the CAG tract. Pathogenic expansions at other loci, such as ATXN3 and THAP11, showed more ancestry-specific distributions. Clinically, individuals with pathogenic ATXN2 and ATXN3 expansions most often presented with typical PD features but frequently showed earlier disease onset and a strong family history of PD. This large-scale, multi-ancestry study comprehensively maps the genetic landscape of pathogenic and intermediate repeat expansions in PD. Our findings confirm a length- and structure-dependent risk association for ATXN2 with PD in the European population and highlight the pleiotropic effects of repeat expansions across the parkinsonian spectrum.
Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder that presents a wide spectrum of clinical phenotypes, posing a fundamental challenge for early and accurate subtyping. This requires a multimodal assessment to identify disease patterns. Robust integration of multi-omics data, brain MRI, clinical biomarkers and cognitive assessments remains challenging, especially when data are missing or incomplete. Existing tools often lack domain-driven reasoning and offer limited interpretability, undermining their clinical utility. This paper presents SPARROW, a multimodal framework that unifies genomic, imaging, clinical and cognitive data in a common semantic knowledge space for PD subtyping. Within SPARROW, specialist modules for omics and MRI analysis provide structured ontology-driven outputs that a large language model-based reasoner then interprets via chain-of-thought reasoning. This approach achieves transparency in subtype decisions by highlighting how each data source contributes to the final classification. Applied to the Parkinson's Progression Markers Initiative (PPMI) dataset, SPARROW achieved superior performance on classification of all subtypes using the baseline visit data in a zero-shot setting. Our findings underscore the potential of SPARROW for accurate and interpretable PD subtyping in clinical settings.
We describe the design of the first non-pharmacological Parkinson's disease prevention trials worldwide: the randomised 'Slow-SPEED' trials. Three trials examine the feasibility and preliminary efficacy of a gamified, remotely administered exercise intervention vs. active control over 18-36 months in complementary prodromal subgroups: iRBD(n = 110; Netherlands), hyposmia(n = 110; United Kingdom) or LRRK2/GBA1 mutation carriers(n = 600; United States). These trials will provide unique insights for large-scale Parkinson's prevention studies. Protocols are registered at ClinicalTrials.gov(NCT06193252[1-5-2024];NCT06600438[9-19-2024];NCT06993142[5-28-2025]).
This prospective study evaluated the prognostic utility of Alzheimer's disease-related plasma biomarkers (phosphorylated tau [pTau217 and pTau231], the amyloid-β [Aβ] 42/40 ratio) and neurofilament light chain (NfL) in 123 Parkinson's disease (PD) patients and 40 controls. Over a mean 5.1-year follow-up, 35 of 109 initially non-demented PD patients (32.1%) progressed to dementia. Plasma pTau217 and NfL levels were elevated, whereas the Aβ42/40 ratio was reduced, in cognitively impaired PD groups versus controls. Baseline pTau217 accurately differentiated dementia converters from non-converters (AUC = 0.877; 95% CI: 0.798-0.956). Patients with pTau217 ≥ 0.268 pg/mL had a higher risk of dementia progression (HR: 5.49; 95% CI: 2.37-12.74). This risk was further elevated in patients in the highest quartile ( ≥ 0.36 pg/mL; HR: 11.35; 95% CI: 2.60-49.59) versus the lowest quartile ( < 0.20 pg/mL). Similarly, the pTau231 cut-off ( ≥ 2.575 pg/mL) predicted an increased risk of dementia (HR: 3.89; 95% CI: 1.67-9.03). Both pTau217 and pTau231 demonstrated high predictive performance in Cox models (C-index: 0.806 and 0.796, respectively). Plasma NfL exhibited longitudinal increases during follow-up. Baseline plasma pTau217 and pTau231 serve as surrogate markers for predicting dementia progression in PD. Further validation of these biomarker cut-off values is warranted.
Parkinson's disease (PD) is often perceived as an elderly condition, overshadowing its impact on younger populations. This study assesses the global, regional, and national burden of early-onset PD (EOPD) in individuals aged 20-49 years from 1990 to 2021 using data from the Global Burden of Disease Study 2021. The estimated annual percentage change (EAPC) quantified temporal trends, while the Socio-Demographic Index (SDI) evaluated socioeconomic development. Decomposition analysis identified factors driving burden changes, while health inequality analysis quantified cross-national disparities. Findings reveal that global incident cases, prevalent cases, and years lived with disability (YLDs) for EOPD more than doubled over three decades. Age-standardized rates per 100,000 increased for incidence (1.46-2.35), prevalence (10.03-14.00), and YLDs (1.65-2.27), with corresponding EAPCs of 1.42%, 1.09%, and 1.05%, respectively. Men had approximately 1.5 times higher burden than women. Health inequalities have worsened, with middle and high-middle SDI regions, especially East Asia and Andean Latin America, exhibiting the fastest growth rates. EOPD burden positively correlated with pesticide use. Rising YLDs were primarily driven by increased prevalence in higher SDI regions and population growth in lower SDI regions. These trends highlight the need for targeted strategies to reduce risk and promote early diagnosis in younger populations globally.
Dopa decarboxylase (DDC) is a candidate biomarker in Parkinson's disease (PD), but its levels are influenced by dopamine replacement therapy (DRT), complicating interpretation. We used high-throughput proteomics to analyze serum and CSF samples from PD patients, individuals with idiopathic REM-sleep behaviour disorder, and controls to assess DRT effects. In serum, DDC increased and prolactin and AOC3 decreased with higher levodopa equivalent daily doses, showing drug class-specific associations. Longitudinally, serum DDC and prolactin levels changed with DRT, while AOC3 remained stable. In CSF, DDC was elevated regardless of treatment, while prolactin was reduced only in treated PD. These results indicate that serum changes in DDC, prolactin, and AOC3 primarily reflect treatment exposure rather than disease biology. Our findings highlight the need to account for medication effects in proteomic studies, identify AOC3 as a novel DRT-sensitive protein, and support the potential of treatment-responsive proteins as pharmacodynamic markers in PD.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss and lipid-rich Lewy bodies containing misfolded alpha-synuclein, implicating lipid dysregulation in pathogenesis. We performed comprehensive lipidomic profiling using liquid chromatography-ion mobility mass spectrometry on paired red blood cell (RBC) and plasma samples from idiopathic PD (iPD) patients (n = 156) and cognitively normal controls (n = 155). We identified significant alterations in 240 RBC and 113 plasma lipids, with elevated sphingomyelins, ceramides, and phosphatidylcholines in RBCs and decreased triacylglycerols, phosphatidylcholines, and phosphatidylinositols in plasma. Multivariate modeling identified an RBC lipid biomarker panel that achieved a discovery-cohort discriminatory AUC of 0.834. Weighted gene co-expression network analysis revealed lipid modules associated with ferroptosis, necroptosis, and sphingolipid and glycerophospholipid signaling, mechanisms converging on alpha-synuclein toxicity and neurodegeneration. This blood-based lipid biomarker panel represents a promising peripheral candidate for iPD detection while providing mechanistic insights into lipid-mediated neurodegeneration.
We investigated environmental determinants of Parkinson's disease (PD) and their attributable burden in a case-control study of 9,887 participants from nine Latin American countries. Logistic regression adjusted for age, sex, and country estimated associations, and population attributable fractions (PAFs) were calculated for modifiable risk factors. Weekly caffeine consumption (adjusted odds ratio [aOR] 0.77, p < 0.0001) and tobacco use for ≥ 5 years (aOR 0.83, p = 0.0009) were inversely associated with PD, whereas severe head trauma (aOR 1.35), occupational pesticide exposure (aOR 1.42), occupational metal exposure (aOR 1.29), rural living (aOR 1.60), and well water consumption (aOR 1.22) increased PD risk (all p < 0.05). Dose-response relationships were observed. The joint PAF was 13.7% (95% CI 9.8-17.3), with higher estimates in El Salvador, Brazil, Colombia, men, and individuals younger than 60 years. Sensitivity and lag analyses yielded consistent results.
Cognitive impairment in Parkinson's disease (PD) remains difficult to stratify using accessible fluid biomarkers, and the metabolic-inflammatory relationships associated with cognitive decline remain incompletely quantified. Here, we examined the relationships among plasma ceramides, inflammatory cytokines, neurodegeneration biomarkers, and cognitive function in PD patients with varying degrees of cognitive impairment, patients with multiple system atrophy (MSA), and healthy controls. MSA was distinguished from PD by higher Cer 18:0/Cer 24:0 and Cer 24:1/Cer 24:0 ratios, despite overlapping cytokine and neurofilament light chain (NFL) profiles. Within PD, worsening cognitive status was accompanied by graded increases in specific ceramide ratios, inflammatory cytokines, and NFL. Cer 24:1/Cer 24:0 was independently associated with cognitive performance (B = - 2.01, P = 0.003). Structural equation modeling identified two association pathways between ceramide-related measures and cognition: a larger direct association (standardized β = -0.223; 60.8% of the total effect) and a smaller inflammation-related indirect association (standardized β = -0.133; 36.2%), whereas pathways involving NFL were not significant. These findings establish a ceramide-centered quantitative framework integrating metabolic and inflammatory dimensions of cognitive impairment in PD, supporting stratified biomarker development.
Parkinson's disease (PD) patients undergo deep brain stimulation (DBS) when other treatments are insufficient. Given the patients' advanced clinical stage, an advanced neuropathological stage is assumed. We examined Lewy pathology in prefrontal cortices (PFCs) of DBS recipients. Virtually no Lewy pathology was seen in PD biopsies. In contrast, postmortem PD PFC samples showed significantly greater Lewy pathology than controls. Thus, DBS patients may be less neuropathologically advanced in progression than previously thought.
G2019S LRRK2 is the most common cause of familial Parkinson's disease (PD) and is associated with sporadic PD, arising from the interplay of genetic predisposition, environmental exposure and aging. Metabolic syndrome is implicated as a risk factor for PD, but the interaction between G2019S LRRK2 and metabolic stress in disease pathogenesis remains unclear. We employed high-fat diet (HFD) feeding to induce metabolic syndrome in aged mutant LRRK2 mice, followed by system-wide characterization, including metabolomic or proteomic profiling, and bulk or single-nucleus RNA sequencing. We find that thymidine and deoxyuridine levels are consistently reduced across tissues in G2019S LRRK2 knockin mice accompanied by increased hepatic expression of thymidine phosphorylase. HFD exposure further unmasks disruptions in purine and energy metabolism in brain and lung of G2019S LRRK2 knockin mice, with midbrain astrocytes and oligodendrocytes exhibiting the most pronounced impairment in oxidative phosphorylation transcriptional pathways. Our findings demonstrate that pre-existing metabolic syndrome unmasks widespread disruptions in systemic nucleotide and energy metabolism and exacerbates mitochondrial dysfunction in G2019S LRRK2 knockin mice. This conditional "two-hit" phenotype underscores the critical role of environmental factors, such as diet, in revealing metabolic vulnerabilities associated with PD-linked genetic backgrounds, and provides potential metabolic targets for therapeutic intervention in PD.