Richard B. Mailman

Background: Progression of substantia nigra pars compacta (SNc) iron content in early‐stage Parkinson's patients (PD) is poorly understood. Objective: To determine if nigral iron measured by quantitative susceptibility mapping (QSM) with zero‐referencing can track disease progression in early‐stage PD. Methods: Thirty‐four early‐stage PD patients and 35 matched controls were recruited. Iron content in the SNc and related regions were obtained using QSM with zero‐referencing at both baseline and 1‐year follow‐up, along with clinical metrics. Results: Of seven clinic metrics and five regional iron measures, only Movement Disorder Society‐Unified Parkinson's Disease Rating Scale‐Part II (MDS‐UPDRS‐II) ( P = 0.046) and SNc iron ( P = 0.0025 for cerebrospinal fluid zero‐referencing; P = 0.014 for whole‐brain zero‐referencing) showed significant changes in PD subjects in the 1‐year epoch. The changes in SNc iron were also correlated with changes in MDS‐UPDRS‐II ( P = 0.004). Conclusion: Nigral iron content measured by zero‐referencing QSM can be used to track disease progression in early‐stage PD over the 1‐year epoch. © 2026 International Parkinson and Movement Disorder Society.

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

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

A bstract: Background: Excessive or unregulated iron in the brain can lead to toxicity via ferroptosis and related mechanisms. Iron accumulation in the substantia nigra (SN) occurs with Parkinson’s disease (PD) progression and has been hypothesized to be an etiological mechanism. Objective: Based 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. Methods: We 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. Results: Experiment 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 Conclusion: Levodopa 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

Chronic occupational exposure to metals in welding fumes has been implicated in the etiology of neurodegenerative diseases (NDDs), including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Changes in microRNA (miRNA) expression have been associated with various neurodegenerative conditions. Circulating miRNAs, in particular, have emerged as promising, minimally invasive biomarkers for diagnosing and monitoring disease progression. This study was designed to characterize the expression of miRNAs in neuronally-enriched serum extracellular vesicles (EVs) among welders and non-welders to explore their potential link to metal concentrations and welding exposure measures and their potential as early diagnostic biomarkers for neurodegeneration. Serum samples from 39 welders and 27 healthy individuals were collected, and EV-enclosed miRNAs were extracted and analyzed. Also, whole blood metal concentrations and welding exposure measurements were obtained. Fifty miRNAs were found to be dysregulated in welders vs. non-welders, of which three (miR-16-5p, miR-93-5p, miR-486-5p) showing reduced expression and two (miR-4281 and miR-4417) exhibiting positive correlations with blood metal concentrations as well as with long- and short-term welding exposure measures. The dysregulation of these miRNAs suggests that exposure to metals could disrupt important biological processes, possibly contributing to an elevated risk of NDDs. These findings highlight the need for further research to validate the causal relationship between exposure to metals in welding fumes, the dysregulation of circulating miRNAs, and their role in neurodegenerative disease development, with implications for miRNA-based biomarkers in early disease detection and prevention.

Levodopa remains the primary treatment for Parkinson’s disease (PD), yet its long-term use has been associated with iron accumulation in the brain, a phenomenon linked to neurodegeneration. We utilize deep machine learning to determine plausible molecular mechanisms that may underlie the effects of levodopa on iron metabolism. Using the DRIFT platform, we performed a proteome-wide target identification of levodopa and uncovered significant interactions potentially involved in cellular iron transport. Pathway analysis revealed that levodopa may influence critical iron-related pathways, including the response of EIF2AK1 to heme deficiency, heme signaling, and ABC-family protein-mediated transport. These findings suggest that levodopa may contribute to iron dysregulation in PD by interacting with iron transporters and modulating iron-related pathways. Because levodopa is used at relatively high doses in PD, our findings provide new insight into secondary effects unrelated to being a precursor of dopamine. This highlights the need for careful consideration of its effects on iron metabolism as a consequence of use in the long-term management of PD. Further experimental validation is required to confirm these interactions, and also to explore potential strategies to mitigate iron-related side effects while preserving therapeutic efficacy.

Background: Parkinson’s disease (PD) therapeutic strategies have evolved since the introduction of levodopa in the 1960s, but there is limited data on their impact on disease progression markers. Objective: Delineate the current landscape of PD progression at tertiary subspecialty care and research centers. Method: Using Accelerating Medicine Partnership-PD (AMP-PD) data harmonized from seven biomarker discovery studies (2010-2020), we extracted: overall [Schwab and England (S&E), PD Questionnaire (PDQ-39)]; motor [Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS)-II and -III and Hoehn & Yahr (HY)]; and non-motor [MDS-UPDRS-I, University of Pennsylvania Smell Identification Test (UPSIT), Montreal Cognitive Assessment (MoCA), and Epworth Sleepiness Scale (ESS)] scores. Age at diagnosis was set as 0 years, and data were tracked for 15 subsequent years. Results: Subjects’ (3,001 PD cases: 2,838 white, 1,843 males) mean age at diagnosis was 60.2±10.3 years and disease duration was 9.9±6.0 years at the baseline evaluation. Participants largely reported independence (S&E, 5y : 86.6±12.3; 10y : 78.9±19.3; 15y : 78.5±17.0) and good quality of life (PDQ-39, 5y : 15.5±12.3; 10y : 22.1±15.8; 15y : 24.3±14.4). Motor scores displayed a linear progression, whereas non-motor scores plateaued ∼10-15 years. Younger onset age correlated with slower overall (S&E), motor (MDS-UPDRS-III), and non-motor (UPSIT/MoCA) progression, and females had better overall motor (MDS-UPDRS-II-III) and non-motor (UPSIT) scores than males. Conclusions: Twenty-first century PD patients remain largely independent in the first decade of disease. Female and young age of diagnosis were associated with better clinical outcomes. There are data gaps for non-whites and metrics that gauge non-motor progression for >10 years after diagnosis.

Background: Patients in late-stage Parkinson’s disease (PD _LS ) are caregiver dependent, have low quality of life, and higher health care costs. Objective: To estimate the prevalence of PD _LS patients in the current United States (US) health care system. Methods: We downloaded the 2010-2022 data from the TriNetX Diamond claims network that consists of 92 USA health care sites. PD was identified using standard diagnosis codes, and PD _LS was identified by the usage of wheelchair dependence, personal care assistance and/or presence of diagnoses of dementia. Age of PD _LS identification, and survival information are obtained and stratified by demographic and the disability subgroups. Results: We identified 1,031,377 PD patients in the TriNetX database. Of these, 18.8% fit our definition of PD _LS (n=194,297), and 10.2% met two or more late-stage criteria. Among all PD _LS , the mean age of PD _LS identification was 78.1 (±7.7), and 49% were already reported as deceased. PD _LS patients were predominantly male (58.5%), with similar distribution across PD _LS subgroups. The majority did not have race (71%) or ethnicity (69%) information, but for the available information, >90% (n=53,162) were white, 8.2% (n=5,121) Hispanic/Latino, 7.8% (n=4,557) black, and LS cohort, 71.6% identified with dementia, 12.9% had personal care assistance, and 4.8% were wheelchair bound. Conclusions: Late-stage patients are a significant part of PD landscape in the current US healthcare system, and largely missed by traditional motor-based disability staging. It is imperative to include this population as a clinical, social, and research priority.

It remains unclear why β-amyloid (Aβ) plaque, a hallmark pathology of Alzheimer’s disease (AD), first accumulates cortically in the default mode network (DMN), years before AD diagnosis. Resting-state low-frequency ( < 0.1 Hz) global brain activity recently was linked to AD, presumably due to its role in glymphatic clearance. Here we show that the preferential Aβ accumulation in the DMN at the early stage of Aβ pathology was associated with the preferential reduction of global brain activity in the same regions. This can be partly explained by its failure to reach these regions as propagating waves. Together, these findings highlight the important role of resting-state global brain activity in early preferential Aβ deposition in the DMN.