Manganese-Enhanced Magnetic Resonance Imaging for Detection of Vasoactive Intestinal Peptide Receptor 2 Agonist Therapy in a Model of Parkinson's Disease

Abstract

Neuroprotective immunity is defined by transformation of T-cell polarity for therapeutic gain. For neurodegenerative disorders and specifically for Parkinson's disease (PD), granulocyte-macrophage colony stimulating factor or vasoactive intestinal peptide receptor 2 (VIPR2) agonists elicit robust anti-inflammatory microglial responses leading to neuronal sparing in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. While neurotherapeutic potential was demonstrated for PD, there remain inherent limitations in translating these inventions from the laboratory to patients. One obstacle in translating such novel neurotherapeutics centers on the availability of suitable noninvasive methods to track disease progression and therapeutic efficacy. To this end, we developed manganese-enhanced magnetic resonance imaging (MEMRI) assays as a way to track a linkage between glial activation and VIPR2 agonist (LBT-3627)-induced neuroprotective immunity for MPTP-induced nigrostriatal degeneration. Notably, LBT-3627-treated, MPTP-intoxicated mice show reduced MEMRI brain signal intensities. These changes paralleled reduced astrogliosis and resulted in sparing of nigral tyrosine hydroxylase neurons. Most importantly, the data suggest that MEMRI can be developed as a biomarker tool to monitor neurotherapeutic responses that are relevant to common neurodegenerative disorders used to improve disease outcomes.

Longitudinal MEMRI analysis of brain phenotypes in a mouse model of Niemann-Pick Type C disease

“…In addition to mass and volume effects, differences in cellular-level Mn 2+ uptake mechanisms in the context of neurodegenerative disease have been reported ( Saar and Koretsky, 2019 ). Hyperintensity in T1-weighted MEMRI has been attributed to astrogliosis in models of inflammation post ischemic stroke ( Kawai et al, 2010 ) and late stage Parkinson’s disease ( Olson et al, 2016 ), and to aberrant Ca 2+ channel activity in models of multiple sclerosis ( Boretius et al, 2008 ). Further mechanistic studies are required to determine the dominant uptake mechanism in this model of progressive NPC.…”

Substantia Nigra Hyperechogenicity Reflects the Progression of Dopaminergic Neurodegeneration in 6-OHDA Rat Model of Parkinson’s Disease

“…Researchers have been interested in looking for suitable markers to assess the process of disease and therapeutic efficacy as the lack of such limited the therapeutic intervention of PD, which had little success. Manganese (Mn)-enhanced magnetic resonance imaging was applied as an imaging biomarker to follow the neurodegeneration of PD (Olson et al, 2016). However, the toxicity of Mn prevented it from being applied to human (Olanow, 2004;Kwakye et al, 2015).…”

“…Parkinson's disease (PD) is the second most common neurodegenerative disease that is age-related and characterized by the loss of dopaminergic neurons and neuroinflammation in the substantia nigra (SN) (Olson et al, 2016). While the causes of PD remain unclear, multiple therapies have been developed, including levodopa supplementation therapy, stem cell and deep brain stimulation, etc.…”

Manganese-Enhanced Magnetic Resonance Imaging: Application in Central Nervous System Diseases

“…The R1 value on MEMRI was proposed as an indicator of PD severity and treatment outcomes (115). In mice with MPTP-induced PD (intraperitoneal administration of Mn 2+ ), an increase in Mn 2+ uptake during the first few days was postulated to be caused by increased astrocyte reactivity due to early striatum terminal degeneration, whereas the enhancement of the MEMRI signal was reduced after anti-inflammatory treatment using vasoactive intestinal peptide receptor 2 agonists, thus facilitating neuronal protection (116). Quantitative AIM-MRI uses a quantitative T1 value (or R1 value = T1 −1 ) to quantify the neuronal activity map of the entire brain, revealing the patterns and locations of changes in neuronal activity in animal models of PD.…”