DOPA Decarboxylase (DDC) has been proposed as a cerebrospinal fluid (CSF) biomarker with increased concentrations in Lewy body disorders (LBDs) and highest levels in patients receiving dopaminergic treatment. Here we evaluate plasma DDC, measured by proximity extension assay, and the effect of dopaminergic treatment in three independent LBD (with a focus on dementia with Lewy bodies (DLB) and Parkinson’s disease (PD)) cohorts: an autopsy-confirmed cohort (n = 71), a large multicenter, cross-dementia cohort (n = 1498) and a longitudinal cohort with detailed treatment information (n = 66, median follow-up time[IQR] = 4[4, 4] years). Plasma DDC was not altered between different LBDs and other disease groups or controls in absence of treatment. DDC levels increased over time in PD, being significantly associated to higher dosages of dopaminergic treatment. This emphasizes the need to consider treatment effect when analyzing plasma DDC, and suggests that plasma DDC, in contrast to CSF DDC, is of limited use as a diagnostic biomarker for LBD, but could be valuable for treatment monitoring.

Blood-based biomarkers are emerging as scalable tools for the diagnosis and monitoring of neurodegenerative diseases, but markers enabling differential diagnosis across major dementias remain limited. Here we show that large-scale plasma proteomics identifies disease-associated signatures across Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia. We analyzed 1,318 plasma samples from well-characterized international cohorts and identified more than 200 dysregulated proteins across disease groups. Glial fibrillary acidic protein showed the strongest increase along the Alzheimer’s disease continuum, whereas integrin alpha-V and integrin alpha-M were consistently reduced in Lewy body disorders, including autopsy-confirmed cases. Elevated neurofilament light chain and lower glial fibrillary acidic protein were associated with frontotemporal dementia. We translated these findings into a 21-protein quantitative multiplex panel and validated it in an independent multicenter cohort ( n = 805). These findings support plasma proteomics as an approach for biomarker-based differential diagnosis and disease staging across major neurodegenerative dementias.

Toxic oil syndrome (TOS) is a multisystemic disease that emerged in Spain in 1981 due to the ingestion of aniline-adulterated rapeseed oil fraudulently sold as olive oil. Although neurological sequelae, including cognitive deficits, have been documented in long-term survivors, it remains unclear whether TOS leads to chronic or progressive neurodegeneration. In this case-control study, we measured blood concentrations of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau 217 (pTau217) in 50 individuals with clinically confirmed TOS and 50 matched healthy controls. Biomarkers were quantified using ultrasensitive immunoassay platforms (Quanterix SIMOA SR-X and Fujirebio Lumipulse G600II). Group differences were evaluated using non-parametric tests, and multiple linear regression was applied to assess associations between biomarkers and clinical variables. While NfL levels were slightly higher in TOS patients (p = 0.025), no significant group differences were observed for pTau217 or GFAP. Age was a consistent predictor of biomarker levels, particularly for GFAP and pTau217, and female sex was independently associated with higher GFAP concentrations. Lower educational attainment was linked to increased NfL levels. Clinical status (TOS vs. control) did not significantly predict biomarker concentrations in any model. These findings suggest no evidence of overt or ongoing neurodegeneration in long-term TOS survivors as detected by current blood biomarkers. However, the possibility of subtle, compartmentalized, or slowly evolving neurotoxic processes cannot be excluded. Future longitudinal studies incorporating serial biomarker assessments, advanced neuroimaging, and oxidative stress markers are warranted to clarify the long-term neurological consequences of TOS and to detect subclinical trajectories of delayed neurotoxicity in this population.

Plasma biomarkers are emerging as noninvasive tools to detect neurodegenerative diseases and monitor treatments in clinical trials. The bPRIDE study investigates blood-based biomarkers to improve the differential diagnosis and molecular staging of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Using proximity extension assay proteomics, we analyzed n=1319 plasma samples from 6 well-characterized cohorts. More than 200 proteins were found dysregulated across the different groups. Levels of GFAP showed the most substantial increase along AD clinical continuum. Levels of Integrin proteins ITGAV and ITGAM were the strongest downregulated proteins in Lewy body disorders and correlated with α-synuclein pathology in an independent autopsy-confirmed cohort (n=129). High NEFL and low GFAP levels were the strongest markers specifically associated to FTD. Findings were translated into a selection of 21 proteins to enable classification and staging models across different causes of dementia with high diagnostic performances within one single assay.

Toxic Oil Syndrome (TOS) was a multisystemic disease that emerged in Spain in 1981 due to the ingestion of aniline-contaminated rapeseed oil. Although neurological sequelae, including cognitive deficits, have been documented in long-term survivors, it remains unclear whether TOS leads to chronic or progressive neurodegeneration. In this case-control study, we measured blood concentrations of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau 217 (pTau217) in 50 individuals with clinically confirmed TOS and 50 matched healthy controls. Biomarkers were quantified using ultrasensitive immunoassay platforms (Quanterix SIMOA SR-X and Fujirebio Lumipulse G600II). Group differences were evaluated using non-parametric tests, and multiple linear regression was applied to assess associations between biomarkers and clinical variables. While NfL levels were slightly higher in TOS patients, the difference was not statistically significant. Similarly, no significant group differences were observed for pTau217 or GFAP. Age was a consistent predictor of biomarker levels, particularly for GFAP and pTau217, and female sex was independently associated with higher GFAP concentrations. Lower educational attainment was linked to increased NfL levels. Clinical status (TOS vs. control) did not significantly predict biomarker concentrations in any model. These findings suggest no evidence of overt or ongoing neurodegeneration in long-term TOS survivors as detected by current blood biomarkers. However, the possibility of subtle or slowly evolving neurotoxic processes cannot be excluded. Longitudinal studies incorporating neuroimaging are warranted to clarify the long-term neurological impact of TOS and to identify potential subclinical trajectories of neurodegeneration in this population.