Nearly 600 conferees gathered in Las Vegas Jan. 25-28 for the 2009 MDA National Clinic Directors Conference, where a number of experts presented a broad range of topics covering neuromuscular disease.
One particular area of focus was ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease). Highlights included discussions of cognitive difficulties, immunization strategies in certain of the familial forms of the disease, and stem cells as possible therapy.
Abnormal behavior in ALS may deserve closer look
Catherine Lomen-Hoerth, who directs the MDA clinic at the University of California at San Francisco (UCSF), reported on fronto-temporal dementia (FTD) and ALS.
In FTD, parts of the brain known as the frontal and temporal lobes, associated with control of reasoning, personality and behavior, language and movement, degenerate and waste away (atrophy). Symptoms may include personality changes, apathy, social withdrawal, difficulty with language, and behavioral disturbances.
FTD is progressive and, as yet, irreversible.
Although cases of severe FTD are uncommon in ALS, Lomen-Hoerth said there's likely a continuum of cognitive and emotional deficits, making it important to look at abnormal behaviors in people with ALS and determine whether they appear to be reactions to the disease or something more.
Importantly, studies have shown shorter survival time in patients with ALS-FTD than in those who have only ALS. One reason for this correlation may be that compliance with treatment recommendations, such as with noninvasive ventilation assistance and feeding tubes, has been shown to be significantly less in those with ALS with FTD. Also typical in ALS-FTD, according to Lomen-Hoerth, are lack of judgment, poor insight into the disease process and difficulty using equipment.
A 20-minute FTD screening test in development at UCSF measures variables in verbal fluency, behavioral function, depression, severity of ALS, pseudobulbar affect (a phenomenon that involves episodes of uncontrollable laughter or crying) and overall cognitive function. It validates cognitive diagnoses in people who have ALS with 80 percent accuracy.
Though an effective tool, screening should not rule out or replace full testing.
Lomen-Hoerth noted that a full neuropsychological battery of tests more effectively identifies cognitive impairment. Such testing includes measurements in language-naming, verbal memory, executive functioning (includes planning, abstract thinking, initiation, inhibition and selective attention), semantic fluency (tests may require the subject to name objects that fit a category), IQ estimate, language and behavioral function. This typically takes nearly three hours to complete.
Immunization strategies offer therapeutic potential in familial ALS
Jean-Pierre Julien from Laval University in Quebec discussed immunization as a means of clearing the harmful molecules of mutated superoxide dismutase 1 (SOD1) protein associated with 20 percent of cases in the familial (inherited) form of ALS (which in turn accounts for 1 percent to 3 percent of all cases of the disease). Such strategies are based on the idea that reduction or neutralization of toxic mutant SOD1 molecules would alleviate the disease.
As noted by Julien and colleagues in a paper published in the Feb. 13, 2007, issue of the Proceedings of the National Academy of Sciences (PNAS), vaccination with human mutated SOD1 delivered by subcutaneous (under the skin) injection delayed disease onset, slowed the rate of motor function loss, and extended survival by approximately 30 days in mice known by the designation G37R and engineered to moderately overproduce mutant SOD1.
However, in G93A mice, which are characterized by severe SOD1 overproduction, the same "active" approach (in which the animal is given a foreign substance to which it may make antibodies) failed to result in significant positive effects.
Researchers suggested the number of anti-SOD1 antibodies that entered the nervous system may have been insufficient to neutralize such extreme levels of mutant SOD1 in the nervous-system tissue. They found a "passive" approach, entailing direct infusion of an antibody solution into the brain, did help ameliorate the disease in these mice.
Work is now in progress to derive antibodies against SOD1 that might be suitable for treatment of patients with familial ALS caused by SOD1 mutations.
Stem cells may have variety of roles in research and treatment
Clive Svendsen of the University of Wisconsin-Madison reported on stem cell therapy development in ALS.
One way to develop this type of therapy would be to turn stem cells into progenitors of motor neurons to replace those lost as a result of ALS. The greatest hurdle, however, may lie in figuring out how to get new motor neurons to connect to muscle.
Other approaches therefore may hold more promise, Svendsen said. They might involve decreasing levels of mutant SOD1 protein, preserving cells that protect neurons and aid their survival, and/or transplanting new non-neuronal support cells that release neuroprotective proteins.
Induced pluripotent stem cells (iPS) are adult cells "regressed" back to a stemlike stage of development from which they can be coaxed down a particular developmental path. They hold great promise for the modeling of disease progression. As therapy, they offer the tantalizing prospect that, when implanted back into the individual from whom they were first derived, they probably won't elicit an immune response.
Numerous trials involving stem cells are in the planning stages.