A dual target molecular MRI probe for noninvasive profiling of pathologic alpha-synuclein and microgliosis in a mouse model of Parkinson's disease

Abstract

Parkinsons disease is characterized progressive deposition of pathologic alpha-synuclein (-syn) aggregates, neuroinflammation, and death of dopaminergic neurons in the substantia nigra projecting to the striatum. Noninvasive in vivo profiling of -syn aggregate accumulation and microgliosis by molecular imaging can provide insights on the underlying mechanisms of disease progression, facilitating the development of effective treatment. However, no classical imaging methods have been successful, despite several attempts. We demonstrate a novel method to noninvasive in vivo profiling of pathologic -syn in combination with microgliosis using molecular magnetic resonance imaging (MRI), by targeting oligomeric -syn in cerebrospinal fluid with nano scavengers (T) bearing a T1-relaxive Gd(III) payload. In this proof-of-concept report we demonstrate, in vitro, that microglia and neuroblastoma cell lines internalize cross-linked T/oligomeric -syn agglomerates. Delayed in vivo T1-weighted MRI scans following intravenous administration in the M83 -syn transgenic mouse line show statistically significant T1 signal enhancement in test mice versus controls. The in vivo data was validated by ex-vivo immunohistochemical analysis which showed a strong correlation between in vivo MRI signal enhancement, Lewy pathology distribution, and microglia activity in the treated brain tissue. Furthermore, neuronal, and microglial cells in brain tissue from treated mice displayed strong cytosolic signal originating from T, confirming in vivo cell uptake of the nano scavengers.