Brain and Systemic Inflammation in De Novo Parkinson's Disease

Abstract

Objective: To assess the presence of brain and systemic inflammation in subjects newly diagnosed with Parkinson's disease (PD).

Background: Evidence for a pathophysiologic role of inflammation in PD is growing. However, several key gaps remain as to the role of inflammation in PD, including the extent of immune activation at early stages, potential effects of PD treatments on inflammation and whether pro-inflammatory signals are associated with clinical features and/or predict more rapid progression.

Methods: We enrolled subjects with de novo PD (n = 58) and age-matched controls (n = 62). Subjects underwent clinical assessments, including the Movement Disorder Society-United Parkinson's Disease rating scale (MDS-UPDRS). Comprehensive cognitive assessment meeting MDS Level II criteria for mild cognitive impairment testing was performed. Blood was obtained for flow cytometry and cytokine/chemokine analyses. Subjects underwent imaging with ¹⁸ F-DPA-714, a translocator protein 18kd ligand, and lumbar puncture if eligible and consented.

Results: Baseline demographics and medical history were comparable between groups. PD subjects showed significant differences in University of Pennsylvania Smell Identification Test, Schwab and England Activities of Daily Living, Scales for Outcomes in PD autonomic dysfunction, and MDS-UPDRS scores. Cognitive testing demonstrated significant differences in cognitive composite, executive function, and visuospatial domain scores at baseline. Positron emission tomography imaging showed increased ¹⁸ F-DPA-714 signal in PD subjects. ¹⁸ F-DPA-714 signal correlated with several cognitive measures and some chemokines.

Conclusions: ¹⁸ F-DPA-714 imaging demonstrated increased central inflammation in de novo PD subjects compared to controls. Longitudinal follow-up will be important to determine whether the presence of inflammation predicts cognitive decline. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; TSPO PET; cognition; cytokine; inflammation.

FIG 1

Alterations in T regulatory (Treg) subset, T non‐regulatory subset, and neutrophil to lymphocyte ratio (NLR) in Parkinson's disease (PD). (A) CD45⁺CD3⁺CD4⁺ cells were gated to CD25⁺CD127⁻ Treg and CD25⁺CD127⁺ non‐Treg subsets. (B) Frequencies of Treg and non‐Treg subsets from PD and control subjects were analyzed and are shown as mean ± standard deviation (SD). *P < 0.05 (Student's t test). Red symbols are females, and blue symbols are males. (C) White blood cell count, including neutrophils, lymphocytes, monocytes, eosinophils, and basophils, was done as part of the complete blood count. The NLR was calculated as percentage of neutrophils divided by the percentage of lymphocytes and is shown as mean ± SD. **P < 0.01 (Student's t test). Red symbols are females, and blue symbols are males.

FIG 2

Parkinson's disease (PD) subjects show higher ¹⁸F‐DPA‐714 binding protein (BP) in the putamen, thalamus, substantia nigra, and cortical brain regions. (A) Comparison of the parametric images of binding potential between the control and PD cohorts. Mean of the BP images for high affinity binders (HAB) subjects is shown here. (B) Raw values for binding potential in control and PD subjects that is not adjusted for sex or translocator protein 18kd (TSPO) genotype. *P < 0.05, **P < 0.01, ***P < 0.001 (Student's t test with Welch's correction). Red symbols are females, and blue symbols are males. Using linear regression to adjust for TSPO genotype and sex, TSPO binding potential is higher in PD subjects in the putamen, thalamus, substantia nigra, and several cortical brain regions.