Development of a Novel Glutamate Receptor Ligand for PET Scans in Neuropsychiatric Systemic Lupus Erythematosus
Condition: Systemic Lupus Erythematosus
MeSH terms: Lupus Vasculitis, Central Nervous System; Lupus Erythematosus, Systemic
Study type: Observational

Summary: 
      Cognitive impairment occurs in as many as 80% of lupus patients and affective disorders,
      depression and anxiety, are also common. Both of these problems contribute significantly to
      disease burden and disability. Associations between serum anti-NMDAR Aab and cognitive and
      behavioral changes in human SLE have remained controversial, however, elevated titers of
      these Aabs in cerebrospinal fluid (CSF) correlate with severe central nervous system
      manifestations, such as coma and psychosis. The aim is to study the progression of disease
      (cognitive and behavioral impairment) over a 2 year period in SLE subjects with
      neuropsychologic and behavioral testing and correlates of disease progression using resting
      FDG-PET and serum Anti-NMDAR Aab. The correlations between hippocampal hypermetabolism,
      Anti-NMDAR Aab and memory impairment observed in the cross-sectional studies will be
      validated by baseline measurements in the proposed studies.
    

Detailed description: 
      Neuropsychiatric lupus 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 N-methyl D-aspartate
      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 Aab access to the brain.

      The investigators' previous cross-sectional FDG-PET studies of resting brain glucose
      metabolism demonstrate robust hypermetabolism in the hippocampus of SLE subjects that
      associates independently with serum Anti-NMDAR Aab titer and impaired memory. Moreover, the
      combination of hippocampus hypermetabolism and elevated serum titers of Anti-NMDAR Aab has a
      higher predictive value for memory impairment than either variable alone. These significant
      correlations must be tested in a longitudinal study to evaluate the utility of FDG-PET as a
      biomarker for Anti-NMDAR Aab-mediated brain damage. The proposed longitudinal studies will
      inform the investigators about correlates of cognitive and behavioral change over time using
      FDG-PET imaging (Aim 1). Additionally, the investigators will explore NMDAR biology with a
      novel PET ligand, [11C]-CNS5161, used to localize and quantify NMDAR activation (Aim 2) and
      explore the role of blood brain barrier (BBB) integrity in cognitive and behavioral
      impairment (Aim 3).
    

Observational model: Cohort
Time perspective: Cross-Sectional
Sampling method: Probability Sample
Study population: 
        24 lupus subjects will be recruited based on the following Inclusion/Exclusion criteria and
        serum anti-NMDAR antibody status. The investigators are not selecting for SLE patients
        known to have cognitive or psychiatric disturbances because attribution of these problems
        is very difficult given the confounding effects of medications, co-morbid disease,
        metabolic disturbances and infections. The investigators are interested in the effects of
        the anti-NMDAR Aab and will stratify lupus subject population on this variable. The PET and
        MRI imaging studies will be performed only during times of stable disease activity and
        medication use to avoid confounding influences of acute changes in disease activity and
        steroids/immunosuppressive medications. The 17 healthy control subjects should have no
        history of chronic illness and be on no prescribed medications other than oral
        contraception. Subjects older than age 55 will also be excluded to avoid confounding
        effects of age on cognitive testing.
      
Keywords: Lupus; SLE