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NEW YORK For years, experts have puzzled over the fact that lupus
patients often experience accelerated declines in thinking and memory
as they age, despite the absence of the usual neurological culprits,
such as neurovascular inflammation or stroke.
Now a husband-and-wife-led team of researchers, including Dr. Bruce
T. Volpe, professor of neurology and neuroscience at Weill Cornell
Medical College and an attending neurologist at NewYork Presbyterian
Hospital and Burke Medical Research Institute in White Plains, say
they have a new approach to this puzzle that may open the door to
treatments that slow or prevent lupus-related cognitive decline.
An immune system antibody that lingers in especially high concentrations
in lupus patients appears to attack and kill brain cells, Volpe's
team reports in the journal Immunity.
"There may be an approach to attenuating the effect of the
antibody, however," he said.
Systemic lupus erythematosus (SLE) is an autoimmune disorder that
causes inflammation, pain and tissue damage throughout the body.
Often chronic, it affects mainly women. There is currently no cure
for lupus, although treatments can ease symptoms.
As treatments lengthened the lives of lupus sufferers, doctors
began to notice increased cognitive decline in many of their aging
patients. However, the brain cell death found in these patients
wasn't always linked to expected causes, such as stroke or inflammation.
Volpe said his work was spurred by a "brilliant" discovery
a few years ago by his wife, Dr. Betty Diamond, of Albert Einstein
College of Medicine in New York. Her team identified a specific
autoimmune antibody, called anti-NR2, which has a special affinity
for glutamate receptors lying on the surface of neurons and other
cells.
Healthy individuals usually rid themselves of most of these auto-antibodies,
but Diamond found high blood concentrations of the antibodies in
40 to 60 percent of lupus patients. In his team's most recent study,
Volpe used a mouse model to determine just how these antibodies
breach the blood-brain barrier, allowing them access to healthy
neurons.
"The temporary inflammation you can get during a cold, the
flu or lupus flare-up can 'open the gate' for antibodies to cross
the blood-brain barrier," he explained, so the mice received
an inflammation-inducing compound to mimic that process.
Seven days after this inflammation occurred, the brains of mice
that were immunized to produce high concentrations of anti-NR2 "had
already lost significant numbers of neurons, especially in the hippocampus,
but also elsewhere throughout the cortex," Volpe said. Behavioral
tests, performed by Dr. Patricio Huerta of New York University,
suggested the mice still functioned well in terms of motor skills
but had suffered memory declines.
Now that the researchers knew lupus-linked auto-antibodies were
attacking and killing brain cells, could they find a way to stop
it?
In another experiment, the multi-institutional team from Weill
Cornell and Einstein injected antibody-laden mice with memantine,
a drug that competes with the antibody for a parking space on each
neuron's glutamate receptor. The treatment stopped the antibody
binding.
"When the memantine was injected, we stopped the neuron's
stress response, and we think it might have effectively preserved
the neuron by interrupting the auto-antibody's access to the receptor,"
Volpe said. "More tests are required before we approach treating
humans, but this approach could lead to new ways of slowing or stopping
the cognitive decline seen in many older lupus patients."
The study has even broader implications, casting the immune system
as a key player in yet other disease processes, this time targeted
neurological damage. "The idea is that these antibodies may
affect cognition -- they certainly do in mice," Volpe said.
The next step, he said, is to use MRI technology to determine the
exact permeability of the blood-brain barrier when it comes to anti-NR2
antibodies. Further experiments will also look closer at "just
how the antibody binds and kills," he said, and what might
be done to prevent that.
The study received funding from the National Institutes of Health,
the Lupus Research Institute, the Burke Medical Research Institute
and the Pew Foundation for Latin American Fellows.
Co-researchers on the study included Lorraine A. DeGiorgio of Burke
Medical Research Institute and Weill Cornell Medical College; Dr.
Betty Diamond, Dr. Hoby Patrick Hetherington, Czeslawa Kowal and
Tsukasa Nakaoka of Albert Einstein College of Medicine; and Dr.
Patricio T. Huerta of the Center for Neural Science, New York University.
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