Searching for Signs

by Margaret Wahl on Mon, 2009-05-18 14:28

Possible ALS biomarkers discussed at American Academy of Neurology meeting

The 61st annual meeting of the American Academy of Neurology (AAN), held in Seattle April 25-May 2, included several ALS-related presentations.

Three concerned identification of biological markers (biomarkers) which indicate the presence or progression of ALS (amyotrophic lateral sclerosis or Lou Gehrig’s disease). Biomarkers are important for diagnosis of the disease and as a way to follow the effects of experimental treatments. They’re a major focus of MDA-supported studies at the ALS Therapy Development Institute in Cambridge, Mass.

Additional presentations included descriptions of disease mechanisms, an analysis of smoking as a risk factor, and a possible new therapeutic avenue.

Neurofilament may correlate with ALS progression

Blood levels of a protein called “neurofilament heavy subunit” were higher, on average, in people with ALS than in the control (unaffected) group, in a study conducted by Kevin Boylan at the Mayo Clinic in Jacksonville, Fla., and colleagues. (Boylan directs the MDA clinic at that institution.)

The researchers measured neurofilament heavy subunit levels monthly for four months in 19 people with sporadic (nonfamilial) ALS and 19 people without ALS. Higher baseline neurofilament levels showed weak evidence of correlating with faster decline in ALS Functional Rating Scale scores over the course of the study.

The investigators said these preliminary results suggest that plasma neurofilament heavy chain levels may correlate with disease progression and that further study of these levels as a potential ALS biomarker are warranted.

Ferritin protein levels correlate with faster disease course, poorer survival

Muddasir Qureshi at Massachusetts General Hospital in Boston, and colleagues, found that levels of ferritin, a protein involved in iron storage, are correlated with survival and rate of disease progression in ALS.

Merit Cudkowicz, an MDA research grantee and director of the MDA ALS Center at Massachusetts General, was part of this research team.

The investigators measured serum ferritin levels in 90 people with ALS and 90 unaffected people and found the levels were higher in the ALS patients. When they followed a group of 99 ALS patients over the course of a year, they found that an increase in ferritin levels was associated with a more rapid decline in muscle strength in the arms and legs. Higher ferritin levels also correlated with reduced survival.

They say further study of the possible role of ferritin in ALS is warranted, particularly in relation to genetic variations.

Loss of skin elasticity goes along with ALS

Dematologist Harvey Arbesman of Williamsville, N.Y., and colleagues, found that skin elasticity was significantly reduced in 40 ALS patients, as compared to a control group of 30 unaffected family members.

Hiroshi Mitsumoto, an MDA research grantee and MDA/ALS Center director at Columbia University Medical Center in New York, was on the study team.

The researchers used a device called a Cutometer, which noninvasively measures the extent to which skin returns to its original position after pressure is applied.

The ALS and control groups were evaluated at baseline and three months later, with skin measurements taken on their arms and back.

At the start of the study, skin elasticity in the arm was significantly less in people with ALS than in the control group. Skin elasticity on the back was significantly correlated with disease progression in the ALS group, becoming less elastic as scores on the ALS Functional Rating Scale and respiratory capacity declined.

The researchers noted that the central nervous system and skin share the same embryologic origin and that many diseases affect both systems. They said further studies are needed, but that skin elasticity could be a valuable, noninvasive way to help detect ALS and assess disease progression.

Smoking correlated with increased risk of death from ALS

Exposure to tobacco smoke appears to increase the risk of dying from ALS, according to a study conducted by Valentina Gallo at Imperial College London and colleagues.

Out of 517,890 apparently healthy subjects who began participating in a European study 10 years ago, 118 have died from ALS.

Those listed as current smokers in the study died from ALS at twice the rate of people who never smoked, while those who said they were former smokers were 1.63 times more likely to die from ALS than those who never smoked.

Those who smoked more than 33 years were almost 2.5 times more likely to die from ALS than those who never smoked.

Small antibody sticks to ALS-causing protein abnormality

Raymond Roos at the University of Chicago and colleagues have developed a protein called a “single-chain antibody” that specifically sticks to one type of ALS-causing genetic abnormality. They say this protein has therapeutic potential against a type of familial (inherited) ALS caused by the so-called A4V mutation in the SOD1 gene. The A4V mutation causes the SOD1 protein to take on highly toxic properties in cells.

Antibodies are proteins generated by the immune system, usually to ward off bacteria, viruses and other threats to health. Laboratory-developed antibodies are widely used to diagnose diseases. Most naturally occurring antibodies have more than one chain and don't enter cells, but laboratory-engineered antibodies with a single chain can enter cells and are sometimes called "intrabodies." The investigators say intrabodies might be effective against various types of SOD1-related familial ALS.

Intrabodies potentially could be developed that would help in nonfamilial (sporadic) ALS too, because it's been suggested that SOD1 protein abnormalities also may be present in this more common form of the disease.

'Splicing' errors may be part of nonfamilial ALS

John Ravits at the Benaroya Research Institute at Virginia Mason Medical Center in Seattle, and colleagues, found that abnormalities in a cellular process called “splicing” were much more common in people with ALS than in people without the disease.

Before a protein can be made from a gene, a rough draft of the protein recipe is first created. The rough draft is made of RNA, which is similar to DNA, and contains sections that the cell splices out before a final protein recipe is made.

Abnormalities in the splicing process can cause disease, and they have been implicated in another motor neuron disease, spinal muscular atrophy. (ALS is a motor neuron disease.)

In nonfamilial (sporadic) ALS, a protein called TDP43 shifts from its proper place in the nucleus, where it normally participates in the splicing process, to outside the nucleus, where it forms clumps.

When Ravits and colleagues analyzed the nervous systems in autopsy samples from 12 people who died of nonfamilial ALS and 10 who died of non-neurologic causes, they found significantly more alternative splicing patterns, at least some of which are likely harmful, in the ALS samples compared to the samples free of neurologic disease.

They concluded that splicing abnormalities are probably part of the ALS disease mechanism.

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