Study data published in NPJ Parkinson’s Disease identified sex-based differences in the activation of peripheral blood monocytes in patients with early Parkinson disease (PD).
In a gene expression study of people with and without PD, both patient status and sex had a marked impact on monocyte activation. These findings emphasize the importance of monocyte activation in Parkinson disease and outline the differential effects of sex on disease pathophysiology.
Recent research suggests that the immune system plays a critical role in the pathogenesis of Parkinson disease. In particular, gene expression studies have demonstrated prominent expression of PD-associated genes in the blood monocytes of affected patients.
To better understand the relationship between peripheral blood monocyte activation and PD, investigators recruited a population of patients with untreated early PD, defined as within 2 years of symptom onset. Patients were age-matched with healthy control group participants.
Blood monocytes were isolated using a negative selection approach; conventional flow cytometry was used to define monocyte populations. RNA-sequencing and gene set enrichment analyses were also performed to determine gene expression patterns in isolated monocytes. A computational model that incorporated patient or control group status, sex, and the interaction between patient or control group status and sex was used to identify differential gene expression patterns of patients and control group participants.
A total of 18 patients with PD and 16 control group participants were enrolled, among whom 11 (61.1%) and 10 (62.5%) were men, respectively. No substantial demographic differences were observed between patients and control group participants. Mean age was comparable between patients and control group participants (P =.21), as well as between men and women (P =.77).
Per flow cytometry analyses, there was moderate evidence for a decrease in the population of classical monocytes, intermediate monocytes, and nonclassical monocytes in patients with PD compared with control group participants.
Computational models found a substantial influence of sex on differential monocyte expression between patients and control group participants. Among women, a total of 347 genes were differentially expressed between the patient and control groups. In men, however, just 15 differentially expressed genes were identified between groups.
Men and women shared only 1 common differentially expressed gene: CEBPG, a transcription factor. In men, this gene was increased in healthy control group participants compared with patients; in women, the gene was more strongly expressed in patients vs control group participants. The lack of overlap in gene expression suggests that the pathogenic process of PD differs substantially by sex.
Pathway analysis revealed a “consistent signature of alterations in inflammatory signaling” among women with PD compared with healthy women. Among men, however, the pattern associated with PD was much more heterogeneous: “the KEGG cytokine-cytokine reception interaction pathway was altered, [as] with females, but other pathways altered…were more diverse.” Thus, in early PD, sex appears to significantly impact the expression of disease-associated genes in peripheral monocytes.
As study limitations, investigators cited the small study cohort and the use of a pooled monocyte analysis technique rather than a single-cell sequencing approach. Even so, these data underscore the importance of systemic monocyte activation in PD and the differential effects of sex on disease pathology.
“Identification of an inflammatory signature in the blood of PD patients opens the door to novel approaches to both biomarkers and treatment,” the study investigators wrote. “As a biomarker, assessment of monocyte activation has potential as a measure of disease activation and possibly the on-target efficacy of immunomodulatory treatment.”
Carlisle SM, Qin H, Hendrickson RC, et al. Sex-based differences in the activation of peripheral blood monocytes in early Parkinson disease. NPJ Parkinsons Dis. Published online April 13, 2021. doi:10.1038/s41531-021-00180-z