May 5, 2005

Progress on Biology of ALS Reported at AAN Meeting

Michael Strong, 2005 Essey Awardee, Speaks on Cognitive Changes in Lou Gehrig’s Disease

[QUICK SUMMARY: Canadian researcher Michael Strong, M.D., winner of the 2005 Essey Award spoke in his acceptance speech at the April meeting of the American Academy of Neurology in Miami, on the current concepts of how ALS destroys the nervous system. Further reports at the meeting gave early hints toward new therapeutics, and included findings on quality of life in ALS, design of clinical trials for the disease, and highlighted progress on understanding the basic biology of the disease process.]

Dr. Michael Strong, recipient of ALSA's 2005 Sheila Essey Award.

Richard P. Essey presented the 2005 Sheila Essey Award for ALS Research to Michael Strong, M.D. on behalf of The ALS Association (ALSA) and American Academy of Neurology (AAN). Strong received the award for his blend of clinical compassion and cutting edge research into the causes and potential treatments for amyotrophic lateral sclerosis (ALS).

A member of ALSA’s national board of trustees, Essey noted in presenting the award to Strong that many investigators have been using the prize funds to help young researchers enter and contribute to the ALS field.

In his acceptance speech at the AAN meeting in Miami, Strong discussed current concepts of how the disease destroys the nervous system and noted that it is hard to do justice to the huge amount of work going on in the area. He focused on the idea that ALS may be a collection of syndromes that manifest as a disorder of key proteins in the nerve cells.

“Many reasons may be leading to the ultimate death of these cells. There are only so many ways a motor neuron can say it is dying, but many ways to get there,” Strong said.

One important association in the disease coming to light in the past few years is that many patients show cognitive changes with ALS. These changes can be subtle, but they lead researchers to conclude that more than the motor neurons are attacked by the disease. This concept may broaden the arena for investigation into the basic nature of the degenerative changes taking place and could point to new treatment strategies.

Researchers find that about half of ALS patients show cognitive changes that can be classified as a fronto-temporal dementia. Fronto-temporal dementia involves personality change that can include excessive emotional and compulsive behavior. Strong suggested that more than 50 percent of ALS patients may show these mild to moderate cognitive changes.

Strong’s research interests have converged on the protein called “tau” that is part of the inner scaffolding of the nerve fibers. Tau typically is deposited in brain as people age, but not in the frontal regions, so finding deposits of tau in the frontal lobes indicates something beyond normal aging is taking place.

Dr. Michael Strong receives Award from Richard Essey

Tau has been implicated in other degenerative diseases of the nervous system. But aspects of tau deposits in ALS are unique to the disease. The main structure of tau is preserved, but added portions to the protein are evident for the tau deposits in ALS.

Strong then spoke in detail about the different proteins that make up the inner scaffold of nerve fibers. The proteins and motor molecules that move cellular cargo along the fibers must meet the extraordinary demands of the extremely long extensions of motor neurons that connect to the muscles. The proteins that maintain nerve fibers are very organized arrays of precisely constructed proteins, all on a microscopic scale. If any one component is made in excess, the structures cannot self assemble properly and becomes disordered. The result inevitably appears to be a motor neuron disease.

Some researchers are gathering evidence for problems in forming the necessary balance of nerve fiber proteins in mouse models of ALS. One idea is that mutant SOD1 is interfering with the proper translation of gene instructions into protein. Another is that the abnormal protein deposits in the disease are producing an inflammatory response that cannot be modulated and kills the cells. Still another is that the cells are not able to handle the messages that they are receiving in a balanced fashion, and so they die. Strong suggested that these all could be different reasons for the same end result, a loss of motor neurons. The shared late consequence in ALS is death of the motor neurons, but there could be different reasons upstream for this loss.

Additional findings that are contributing to better understanding of ALS, reported at the 2005 AAN meeting in Miami, are detailed below.

SOD1 Mutation’s Toxicity

Studies reported in posters at the meeting show how the protein change in some inherited cases of ALS might be producing toxic effects. Han-Xiang Deng, M.D., Ph.D., working with Teepu Siddique, M.D., at Northwestern University, Chicago, found that two key sites in one mutated version of the SOD1 protein are crucial to toxicity. Changing these sites by replacing the responsible amino acids, in a transgenic mouse bearing the mutation, prevents SOD1 from forming abnormal deposits in their cells. The mice also do not show motor neuron disease.

In addition, Deng reported that stubborn clumps of SOD1 that do not dissolve in lab tests appear at both the inner and outer membranes of mitochondria, the organelles that power cell processes. Previously implicated in ALS, the mitochondria with these aggregates are swollen and visibly damaged. These observations support several published studies that show mutant SOD1 is associated with mitochondria. If researchers learn exactly what is toxic about mutated SOD1, they can work towards targeted therapy to correct the damage in the disease.

Early Hints on New Therapeutics

Now that scientists recognize that mutant SOD1 is toxic, they are trying to lower its content inside cells. Wu-Yen Hung, Ph.D., working with Siddique’s group, reported on six potential therapeutic agents for ALS tested in fibroblast cells from SOD1 mutant mice. The drugs are from a library of 2000 FDA approved compounds.

Hung indicated that it is too early to discuss any particular drug, as data only reflect their ability to lower production of mutant SOD1 by the cells. It is a long way from a drug that works in cells in a dish to a therapeutic that is safe and effective. These researchers are looking for a wide range of categories of compounds that might be candidate treatments. They are now testing the candidates by treating live mice that have mutant SOD1. A drug that delays the onset of symptoms in the mouse or extends survival time would be a potential therapeutic candidate.

Gene Protects Motor Neurons

Erik Pioro, M.D., Ph.D. director of the ALS Center at the Cleveland Clinic, is collaborating with ALSA-funded investigator Michael Coleman, Ph.D., at the Babraham Institute in Cambridge, U.K., to study the effect of a gene that protects the nervous system in mouse models of motor neuron disease. The Wld^S gene mutation delays disintegration of the nerve fibers and prevents loss of function, as well as visible damage to the cell body of motor neurons in a model of motor defects. Grip strength was preserved in the presence of the gene, compared to Wobbler mice without the Wld^S  gene. Two Wld^S  genes were better at preserving grip than a single gene copy.

The Wobbler mouse model recreates some aspects of ALS. It is not a perfect picture of the disease, but can give some information that could be helpful for therapeutic strategy. Understanding how the Wld^S   gene is protective in this mouse could point to therapeutic avenues for ALS.

New Findings on VEGF

In talks following the presentation of the Essey award, Mohammad Saeed, M.D., working with Siddique’s group and collaborators, reported on a search for variants of the gene coding for VEGF (vascular endothelial growth factor) in people to see if any varieties of the gene that can occur in populations of people might be a risk factor associated with ALS. One variant of the VEGF gene did appear more often in people with early onset of ALS, Saeed reported. It is possible that this particular version of the VEGF gene could be associated with increased risk for the disease. The researchers did not reproduce findings from Europe, reported in 2003, that a variant of the VEGF gene is linked with ALS, and others have also failed to replicate that association http://www.alsa.org/news/article.cfm?id=505.

People with advancing ALS are often not getting sufficient oxygen as their breathing weakens. A factor that should recognize the lowered oxygen in tissues apparently is not responding as it should in ALS patients, according to results presented in a poster by French researcher Caroline Moreau, M.D., working with Nicolas Just and P. Alain Destee at the Universitaire de Lille. The trophic factor, vascular endothelial growth factor (VEGF), is already implicated in animal models of the disease and in genetic studies of ALS patients. VEGF responds to low oxygen by prompting growth of blood vessels. It also may help nerve cells withstand lowered oxygen. Moreau’s findings shed more light on VEGF’s role in ALS.

VEGF was lower in blood and fluid surrounding the brain and spinal cord in ALS patients with lowered tissue oxygenation, compared to patients with other neurological conditions who also happened to have lowered oxygenation. The patients with neurological conditions other than ALS had increased VEGF in the body fluids, as the factor properly registered lack of oxygen. Although this is early data, the study suggests that patients should have respiratory assistance early to protect their motor neurons. Clinicians recommend that breathing be assisted through means such as Non-Invasive Ventilation (NIPPV), as early as possible in ALS.

Quality of Life in ALS

Quality of life for ALS patients increases with use of multidisciplinary clinics according to a presentation given by Dutch researcher Leonard Van den Berg, M.D., of the Rudolf Magnus Institute for Neurosciences, in Utrecht, the Netherlands. The investigators conducted interviews of 208 patients and their caregivers. Of these patients, 75 received care outside of a specialized ALS center. Better mental health and social functioning appeared for those patients treated at the multidisciplinary clinics. Comment from the audience suggested that this kind of data is needed for U.S. patients to convince insurance companies that the multidisciplinary approach is cost effective. ALS patients can receive care outside of a multidisciplinary clinic and maintain a high quality of life.

Design of Clinical Trials for ALS

In another session devoted to clinical findings in ALS, Adam Czaplinski, M.D., working with Stanley Appel, M.D., at Baylor University in Houston, spoke to the use of database records from past ALS trials, as a cost effective alternate to concurrent control groups in clinical trials. Appel, a former Essey awardee, used the award funding to support Czaplinski’s efforts. The strategy was to match ALS patients in a Baylor database, with the control patients who had been assigned to placebo in a prior clinical trial of the potential therapeutic, IGF-1.

The two groups of patients could be matched for characteristics such as age, sex, and initial clinical measures at the start of the trial. Czaplinski said that patients who progressed more slowly were likely to continue to do so. Those with more rapid deterioration at the start of study, also tended to have their disease continue to progress rapidly.

One limitation to mining a database for controls for new studies is that patients after 1999 are tending to progress more slowly in general and survive longer. Since the aim is to avoid exposing large numbers of ALS patients to ineffective therapy, a database instead of concurrent controls could work for pilot trials as a first step, but the definitive trial for any new ALS therapeutic approach will be still be a randomized, placebo controlled trial, Czaplinski concluded.

A way to follow patients during clinical trials is offered by a measure of nerve function called MUNE, motor unit number estimate. This estimate of how many nerves are working is made by recording electrical signals. Jeremy Shefner, M.D., Ph.D., State University of New York in Syracuse, reported in a talk at the meeting that MUNE has potential to serve as a marker of progression in ALS, in clinical trials and in animal studies of candidate treatments. Motor unit number estimation by electrophysiology correlated with onset and duration of disease in animals, Shefner reported. MUNE has too much variation to use as a measure of disease progression in a single patient, he continued, but MUNE could be a marker of drug effect in groups of patients in clinical testing.

Seeing ALS Damage with MRI

Camilla Blain, M.D., part of a research team at Kings College, in London, U.K. working with Nigel Leigh, M.D., and collaborators, spoke about the use of a type of brain imaging that can look at changes in the bundles of nerve fibers within the brain and spinal cord. The magnetic resonance imaging, called diffusion tensor imaging, can tell by the signal from water molecules within the brain that the nerve tracts are intact or are damaged. The group studied 22 ALS patients and compared them to 24 control individuals. The ALS patients were different on scans compared to controls.

Only three patients completed three scans over time. The researchers did not see any significant reduction in the scan parameters, perhaps because these particular patients were well advanced in their disease or very sick patients did not come back for follow up.

Diffusion tensor imaging in another report, again showed damage to motor cortex and the tracts sending nerve fibers to the spinal cord, in 20 ALS patients and 20 matched controls studied by the group working with Hiroshi Mitsumoto, M.D., at Weill Cornell Medical Center in New York City. Notable also was the widespread involvement of the frontal lobes in these patients.

Sanjay Kalra, M.D., at the University of British Columbia, Vancouver, presented in a poster the finding that a specific signal from living neurons, a marker called n-acetyl aspartate (NAA), can be measured by imaging studies, as was also reported by the Mitsumoto group. Kalra and colleagues also sought another marker, myoinositol, that indicates the presence of glia. Together, these signals provide a ratio that is a more powerful predictor for ALS progression than either alone. To see these signal molecules requires a strong magnet in the MRI scanner. Kalra said that the findings are the first imaging study to show correlation of imaging of ALS with the clinically used, functional rating scale for ALS patients (ALSFRS).

The ability to see changes in the nervous system as ALS progresses would be quite useful for clinicians and for testing therapeutics. But still at issue is the timing of such imaging. The typical delays to diagnosing ALS may leave patients too far along for imaging to be a realistic tool. Earlier use of imaging, earlier diagnosis, and better imaging techniques are all hopeful developments for the field.