The role of microglia in Parkinson's disease cognitive and motor impairment

Parkinson’s disease (PD), PD-mild cognitive impairment (PD-MCI), and PD-dementia cause substantial loss of quality of life and healthcare utilization. PD is a heterogeneous pathoetiological syndrome, and while individual genetic subtypes are being targeted with gene-specific disease-modifying strategies, “sporadic” PD needs to be slowed by targeting mechanisms common across many forms of PD. Multiple lines of evidence support activation of microglia as a critical step in the cascade of events in PD onset and progression. While autopsy studies show microglial proliferation and activation in end-stage disease, we need to better tools to evaluate microglial proliferation and activation in vivo in order to explore a causal relationship between this process and disease progression. So far, microglial state has been imaged indirectly with radiotracers binding the mitochondrial Translocator Protein 18 kDa (TSPO), which can represent mitochondrial activation of any cause and TSPO ligands have several major caveats that limit their use widely. We developed a microglial-specific radioligand targeting the colony stimulating factor 1 receptor (CSF1R), [11C]CPPC, and preliminarily suggest a correlation between its binding and motor and cognitive disease severity in patients with early PD. The objective of this proposal is to better understand the relationship between [11C]CPPC binding and cognitive and motor severity in PD and PD-MCI while exploring correlations with pathology biomarkers (α-synuclein, β- amyloid, tau), peripheral immune function and [11C]CPPC. Aim 1 is to determine whether CSF1R density is increased in PD patients with more advanced motor and cognitive dysfunction. We hypothesize that A) persons with early PD will have higher [11C]CPPC binding in the brainstem, striatum, pallidum, and thalamus than age-similar subjects with no known neurodegenerative or autoimmune disorders and within PD, those with the highest two quartiles of motor disability will have higher [11C]CPPC binding than those below the median and B) in persons with PD or PD-MCI, CSF1R density will inversely correlate with verbal fluency, executive, and global cognitive dysfunction in regions known to be involved with cognitive dysfunction (frontal, temporal, parietal, and anterior and posterior cingulate cortices). Aim 2 is to assess whether CSF1R binding with [11C]CPPC is associated with peripheral blood markers of immune function and neurodegeneration that correlate with inflammation and disease progression, respectively. We hypothesize that A) those with the highest tertile of CSF1R binding in specific motor regions will have higher percentages of CD4+ non-regulatory T-cells and higher neutrophil-to-lymphocyte ratio on spectral flow cytometry and unique single cell RNAseq signatures in peripheral blood mononuclear cells, relative to those with the lowest tertile of regional CSF1R binding and that B) [11C]CPPC binding in motor and cognitive regions will correlate with plasma markers of neurodegeneration and cognitive impairment, including amyloid-β42/40 ratio, p-tau181, total tau, glial fibrillary acidic protein, and neurofilament light chain while CSF1R will be highest in those with α-synuclein seeding.