RESUMO
Parkinson's disease (PD) is the second most common neurodegenerative disease in the United States. Decades before motor symptoms manifest, non-motor symptoms such as hyposmia and rapid eye movement (REM) sleep behavior disorder are highly predictive of PD. Previous immune profiling studies have identified alterations to the proportions of immune cells in the blood of clinically defined PD patients. However, it remains unclear if these phenotypes manifest before the clinical diagnosis of PD. We utilized longitudinal DNA methylation (DNAm) microarray data from the Parkinson's Progression Marker's Initiative (PPMI) to perform immune profiling in clinically defined PD and prodromal PD patients (Prod). We identified previously reported changes in neutrophil, monocyte, and T cell numbers in PD patients. Additionally, we noted previously unrecognized decreases in the naive B cell compartment in the defined PD and Prod patient group. Over time, we observed the proportion of innate immune cells in PD blood increased, but the proportion of adaptive immune cells decreased. We identified decreases in T and B cell subsets associated with REM sleep disturbances and early cognitive decline. Lastly, we identified increases in B memory cells associated with both genetic (LRRK2 genotype) and infectious (cytomegalovirus seropositivity) risk factors of PD. Our analysis shows that the peripheral immune system is dynamic as the disease progresses. The study provides a platform to understand how and when peripheral immune alterations occur in PD and whether intervention at particular stages may be therapeutically advantageous.
RESUMO
BACKGROUND AND OBJECTIVES: Multiple sclerosis (MS) is a heterogeneous disease, and its course is difficult to predict. Prediction models can be established by measuring intrathecally synthesized proteins involved in inflammation, glial activation, and CNS injury. METHODS: To determine how these intrathecal proteins relate to the short-term, i.e., 12 months, disease activity in relapsing-remitting MS (RRMS), we measured the intrathecal synthesis of 46 inflammatory mediators and 14 CNS injury or glial activation markers in matched serum and CSF samples from 47 patients with MS (pwMS), i.e., 23 RRMS and 24 clinically isolated syndrome (CIS), undergoing diagnostic lumbar puncture. Subsequently, all pwMS were followed for ≥12 months in a retrospective follow-up study and ultimately classified into "active", i.e., developing clinical and/or radiologic disease activity, n = 18) or "nonactive", i.e., not having disease activity, n = 29. Disease activity in patients with CIS corresponded to conversion to RRMS. Thus, patients with CIS were subclassified as "converters" or "nonconverters" based on their conversion status at the end of a 12-month follow-up. Twenty-seven patients with noninflammatory neurologic diseases were included as negative controls. Data were subjected to differential expression analysis and modeling techniques to define the connectivity arrangement (network) between neuroinflammation and CNS injury relevant to short-term disease activity in RRMS. RESULTS: Lower age and/or higher CXCL13 levels positively distinguished active/converting vs nonactive/nonconverting patients. Network analysis significantly improved the prediction of short-term disease activity because active/converting patients featured a stronger positive connection between IgG1 and CXCL10. Accordingly, analysis of disease activity-free survival demonstrated that pwMS, both RRMS and CIS, with a lower or negative IgG1-CXCL10 correlation, have a higher probability of activity-free survival than the patients with a significant correlation (p < 0.0001, HR ≥ 2.87). DISCUSSION: Findings indicate that a significant IgG1-CXCL10 positive correlation predicts the risk of short-term disease activity in patients with RRMS and CIS. Thus, the present results can be used to develop a predictive model for MS activity and conversion to RRMS.