Meggan Mackay, MD

The Feinstein Institute of Medical Research, NY

2011 Human Lupus Biology
2012 Biomarkers, Central Nervous System

Meggan Mackay, MDDevelopment of a novel glutamate receptor ligand for PET scans in NP-SLE

The Study and What it Means for Patients

“This brain imaging study is the first testing whether autoantibodies against neurotransmitter receptor NMDA impair its activation. With Feinstein neuroimaging experts, we’re using a new radiochemical tracer that binds the NMDA receptor to visualize receptor activity in the brains of lupus patients with this autoantibody. If successful, the technology will be developed as a new biomarker to diagnose neuropsychiatric lupus and monitor therapy response.”

Summary:
Cognitive problems, such as memory disturbances and difficulty concentrating, and mood disorders, such as depression, anxiety, are two common neuropsychiatric syndromes in lupus patients that impact severely on quality of life. Exactly how lupus affects the brain is unclear, but earlier LRI-supported research by Feinstein Institute scientist has shown that an lupus autoantibody directed against a neurotransmitter receptor on brain cells (the N-methyl d-aspartate – NMDA receptor) causes disruption of brain cells in mice resulting in memory and behavioral problems. Using my experience in medical imaging, I am collaborating with Feinstein colleagues expert in lupus to use a new radiochemical tracer that binds the NMDA receptor to visualize receptor activity in the brains of lupus patients who have this autoantibody.

Scientific abstract:
Neuropsychiatric SLE (NPSLE) is comprised of numerous, complex central and peripheral nervous system symptoms whose pathophysiologic mechanisms remain poorly understood. Cross-reactive anti-dsDNA antibodies have been shown to bind NR2A/NR2B subunits of the NMDA receptor (NMDAR) on neurons and synergize with glutamate in a concentration dependent manner to either modulate receptor function or cause an excitotoxic, non-inflammatory neuronal death. Mice immunized to express anti-NMDAR Aab demonstrate a causal relationship between anti-NMDAR Aab and persistent behavioral and cognitive neuropathology following compromise to the blood brain barrier (BBB) which is necessary for autoantibody access to the brain. The overarching hypothesis of this proposal is that [11C]-CNS5161, a Positron Emission Tomography (PET) ligand used to localize and quantify NMDAR activation will identify glutamatergic dysfunction in lupus patients stratified for the presence of autoantibodies directed against NMDAR. We will study 3 groups of subjects at rest and following an activation task using [11C]CNS-5161 PET imaging: SLE patients with and without elevated serum titers of anti-NMDAR autoantibody and healthy controls. Studies will be done at baseline and 12 months. Information from these experiments will be used to develop [11C]-CNS5161 as a new imaging biomarker for neuropsychiatric lupus (NPSLE) and establish an objective baseline for future treatment.