The diagnosis of PD is based on clinical characteristics because there are no reliable blood tests for early diagnosis or to follow the progressive course of the disease. Along with the gradual loss of dopamine neurons and the intracellular accumulation of abnormal material (Lewy bodies), the brain simmers with inflammatory processes. Since the brain’s immune response can be mirrored by alterations in the peripheral immune system, we will study white blood cell (T-cell) receptor variations and immune proteins to trace the trajectory of disease and to potentially serve as a pre-clinical biomarker of PD.
A total of 240 subjects will be included in this study. (60 subjects from each of 3 stages of disease — mild, moderate and severe PD -- and 60 age- and sex-matched healthy controls.) We will draw whole blood from each subject. Part of whole blood will be used to determine each T cell lymphocyte population with Flow-cytometry. Two special subtypes of T cells (CD4 and CD8 T cells) will be separated for mRNA isolation. The T-cell receptors (TCR) of CD4 and CD8 will be amplified with real-time polymerase chain reaction (RT-PCR), then the PCR product will be separated on agarose-gel. Pictures will be taken and the difference among samples can be differentiated by the property of bands. We expect to find specific patterns of TCR that correlate with stage of disease.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
By the time the clinical diagnosis of PD is made, the underlying disease process has been smoldering for many years. The discovery of a simple blood biomarker of disease progression will be useful in studies designed to impact the disease process and to slow or reverse the disease. In addition, blood tests based on immune markers may also be useful as an early indicator of disease pathology, even before disease becomes clinically evident. This would allow early recognition of the disease and permit a timely intervention to delay onset or even prevent the disease.
We expect to develop a blood test to profile markers of the immune system that correlate with clinical stages of PD. In particular, we predict there will be less diverse changes in the TCR chain for CD4 or/and CD8 T cell populations and a cluster of specific gene sequences found to respond to antigen stimulation (like alpha synuclein). Once we identify a specific panel of TCR changes that change as disease progresses, these immune system markers will serve as a biomarker for PD diagnosis and prognosis.
In this MJFF funded project, we have sought to identify a specific biomarker for PD in peripheral blood samples. We have shown that T-cell receptor (TCR) clonality in CD4 T cells may serve as a stable and specific marker for PD. Also, plasma alpha synuclein levels are related to PD onset, and we further confirmed that alpha synuclein peptide can drive TCR clonality. Our discovery may also help to identify a novel therapeutic target for PD.