α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The clinical diagnosis of motor PD is preceded by a prolonged premotor phase with significant neuronal damage. Identifying early biomarkers is crucial for developing effective therapies to slow or prevent PD progression. This study investigated the potential role of α-synuclein (α-syn)-specific T cell reactivity as an early indicator of PD. Previous research by the authors demonstrated the presence of α-syn-reactive T cells in some PD patients, suggesting a potential autoimmune component. This study aimed to analyze α-syn-specific T cell responses longitudinally in a single individual and cross-sectionally in two independent cohorts of PD patients and healthy controls to determine the temporal association between these immune responses and PD pathogenesis.

The concept of an extensive prodromal phase in PD is supported by the frequent occurrence of non-motor symptoms like hyposmia, constipation, mood changes, and REM sleep behavior disorder, which can precede motor symptoms by decades. However, their direct association with PD remains unclear due to the overlap with other neurodegenerative processes. Previous studies have explored inflammatory manifestations in PD, and a recent study by the authors' team identified α-syn-specific T cells in some PD patients, highlighting the potential involvement of autoimmune mechanisms. The heterogeneity of T cells, characterized by their cytokine secretion profiles (e.g., IFNγ, IL-4, IL-10), makes it important to investigate their diverse roles in PD progression. Studies in other autoimmune diseases have shown changes in T cell populations over the disease course, suggesting that similar patterns might exist in PD.

The study employed two approaches: (1) a longitudinal case study of a single individual with cryopreserved blood samples collected over many years, from before to after their PD diagnosis in 2009; (2) a cross-sectional study of two independent cohorts of PD patients and age-matched healthy controls. Peripheral blood mononuclear cells (PBMCs) were stimulated with an α-syn epitope pool, and cytokine production (IFNγ, IL-5, IL-10) was assessed using FluoroSpot and intracellular cytokine staining (ICS) assays. The longitudinal case study allowed for the examination of changes in α-syn-specific T cell responses over time. The cross-sectional cohorts allowed for comparisons of α-syn-specific T cell reactivity between PD patients and healthy controls. HLA typing was performed to explore potential genetic associations. Clinical data, including age, sex, cognitive function (MoCA), motor function (UPDRS-III), and levodopa equivalent dose (LED), were collected to identify potential correlations with α-syn-specific T cell reactivity. Statistical analyses, including Mann-Whitney tests and Fisher's exact tests, were used to compare responses between groups and assess correlations between variables.

The longitudinal case study revealed the presence of α-syn-specific T cell reactivity years before the onset of motor symptoms, with the response declining after PD diagnosis. In the cross-sectional studies, α-syn-specific T cell responses were significantly higher in PD patients compared to healthy controls shortly after diagnosis, declining with time since diagnosis. A significant association was observed between α-syn-specific T cell reactivity and age, with older patients showing a higher frequency of responses. A positive correlation was found between low LED (<1000 mg/day) and α-syn-specific T cell reactivity. The majority of responses were mediated by CD4+ T cells producing IFNγ and IL-10. IL-10 production was not associated with classic regulatory T cells (Tregs), suggesting a different regulatory T cell subset might be involved. No significant association was found between α-syn-specific T cell reactivity and cognitive function or motor scores. Combining age, LED, and time from diagnosis improved the classification of PD from non-PD, achieving nearly 70% accuracy.

The findings provide evidence that α-syn-specific T cell responses are associated with the preclinical and early stages of PD. The presence of these responses before the onset of motor symptoms supports the hypothesis that immune mechanisms play a role in PD pathogenesis. The decline in reactivity after diagnosis could reflect the exhaustion of T cells or the shifting balance of the immune response. The positive correlation with age and low LED could suggest that the immune response contributes to the disease process, but its impact diminishes as the disease progresses and medication levels increase. The lack of correlation with UPDRS scores supports the idea that T cell reactivity is more important in the early preclinical phase than later disease stages. Future studies are needed to investigate the mechanisms underlying this immune response and the potential of T cell monitoring for early diagnosis and risk stratification. The identification of different T cell subsets and their roles in PD pathogenesis requires additional research.

This study confirms the association of α-syn-specific T cells with PD, demonstrating their presence in preclinical and early motor PD. Monitoring α-syn-specific T cell reactivity in at-risk populations could help identify individuals for preventive treatments and immunotherapeutic approaches. Further research is needed to elucidate the underlying mechanisms and refine the potential of this immune response as a biomarker for early diagnosis and treatment.

The study included a relatively large sample size, but the PD patients and healthy controls were unbalanced for sex. The cross-sectional nature of the cohorts limits the ability to make definitive causal inferences. Potential misdiagnosis of PD in early disease might influence the results, although the cohorts were evaluated by specialists. Further studies with longitudinal designs and larger, more balanced cohorts are needed to confirm these findings and explore the causal relationships.