A protein fragment called 12.5 kda cystatin may generate first simple test for multiple sclerosis

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Public release date: 3-Mar-2006

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s Hopkins Medical Institutions

A protein fragment called 12.5 kda cystatin may generate first simple

test for multiple sclerosis

s Hopkins scientists report the discovery of a protein found only

in cerebrospinal fluid that they say might be useful in identifying a

subgroup of patients with multiple sclerosis (MS) or identifying

those at risk for the debilitating autoimmune disorder.

MS strikes over 10,000 Americans each year, most of whom are women,

and causes weakness, numbness, a loss of muscle coordination, and

problems with vision, speech, and bladder control. It is a disorder

in which the immune system destroys myelin, the covering of nerves

that helps transmit signals. Cerebrospinal fluid (CSF) is the watery

fluid that surrounds and cushions the brain and spinal cord.

The federally funded Hopkins research, reported in the February issue

of the ls of Neurology, is important, the researchers say,

because unlike other autoimmune diseases in which the body attacks

its own tissues, MS cannot be diagnosed with a simple blood or other

test.

While it is recognized that there might be several forms of MS,

laboratory-based tests need to be developed to diagnose these subtypes.

" There is the possibility now that the protein we identified, 12.5

kDa cystatin, can be used to diagnose MS, perhaps in its earliest

stages, and also to monitor treatment by measuring its levels in

CSF, " says Avindra Nath, M.D., a professor in the Department of

Neurology at The s Hopkins University School of Medicine and lead

author of the study.

Working with human CSF, the Hopkins team showed that 12.5 kDa

cystatin is a breakdown product of a larger protein called cystatin C

or 13.4kDa, which in turn blocks activity of some enzymes, including

cathepsin B. Cathepsin B has been linked to demyelination-the

destruction of the nerve sheath. The term kDa refers to Kilodalton,

the weight of one molecule of a substance.

" In fact, those patients who had more of the breakdown product of

12.5 kDa cystatin also seemed to have the highest cathepsin B

inhibition, " Nath said.

The investigators made their finding using a sophisticated technique

called SELDI-time-of-flight mass spectroscopy that can find one

specific protein in a complex mixture based on its weight. They used

it to examine CSF samples from 29 patients with MS or pre-MS symptoms

such as numbness on one side; 27 patients with transverse myelitis, a

painful inflammation of spinal cord nerves; 50 infected with the AIDS

virus (which can cause nerve damage); and 27 with other neurological

diseases. The Hopkins scientists analyzed CSF instead of blood

samples because CSF better represents local events in the brain than

does blood, according to Nath. And the high concentrations of many

proteins in the blood can mask proteins that might be biomarkers for

MS, he added.

The team found that the 12.5kDa fragment of cystatin C occurred in

CSF samples from two-thirds of patients with MS or the pre-MS

conditions. Moreover, although total cystatin C levels in MS patients

were not different from control patients without the disease,

patients with MS had a larger proportion of the 12.5 kDa compared to

13.4 kDa cystatin C than did other patients. Thus, the presence of

the 12.5 kDa fragment might identify a subgroup of MS patients.

http://www.eurekalert.org/pub_releases/2006-03/jhmi-apf030206.php