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Researchers From Around the World
Present Findings at International
Conference on ALS
Nov. 30 Sessions

by Margaret Wahl

The 17th International Symposium on ALS/MND (Amyotrophic Lateral Sclerosis/Motor Neurone Disease) is being held in Yokohama, Japan, from Nov. 30 through Dec. 2, 2006.

Sharon Hesterlee, MDA Vice President-Translational Research, and Valerie Cwik, MDA Vice President-Research, as well as Annie Kennedy, Director of MDA’s ALS Division, are attending the meeting, at which several MDA-supported researchers are presenting findings.

Highlights from the Nov. 30 presentations follow.

Genes and ALS

Several presentations concerned the role of various genes in causing or contributing to ALS.

Scientists from the Translational Genomics Research Institute (TGen) of Phoenix, Ariz., announced results of a high-tech scan of all the genes of 1,200 people with and 2,000 people without ALS. The massive project, supported by a $652,000 grant from MDA’s Augie’s Quest, a fast-track ALS research program, in collaboration with TGen, is expected to open up a previously unexplored area of ALS research. The researchers identified significant differences between ALS patients and healthy people in genes that have to do with how nerve fibers attach to muscle fibers (see “Scan of Entire Human Genome,” Nov. 30), a process that until now hasn’t received much attention as a contributor to ALS.


Japanese scientists from Nagoya University Graduate School of Medicine announced they had identified significant differences in gene activity between 14 ALS-affected and 13 unaffected subjects. This type of study, called an “expression array,” doesn’t look at changes in gene structure, but rather in gene activation, or expression, associated with a particular condition.


They found decreased activity in 3 percent of the genes they examined, including those associated with transportation of materials inside cells, as well as those associated with the process of reading genetic instructions and with the formation of molecules on cell surfaces. They found increased gene activity in 1 percent of the genes they examined, including some of the genes involved in cell death and cell death inhibition, as well as some for nerve-nourishing proteins called neurotrophic factors.


A U.S. group, with MDA funding to Martina Wideau-Pazos at the University of California-Irvine, identified a pattern of gene expression that’s likely to be associated with neurodegeneration in general. They analyzed tissues from two types of mice, one with a genetic form of ALS and one with another form of neurodegeneration.


A Dutch team described its analysis of 19 ALS patients and 19 healthy subjects, in which it found discrepancies in the expression of 74 genes. Some of these genes are involved in how cells read genetic instructions, how cells transport substances and how proteins are activated.


Researchers in the United Kingdom examined mice with a genetic form of ALS at different time points. They found an early adaptive response by ALS-affected cells, followed later on by cell death.
ALS ‘Hot Spots’

A University of California-San Diego group reported that the prevalence of ALS on the Pacific island of Guam (about 3,300 miles west of Hawaii), which was far above average between 1945 and 1960, has steadily declined since then. Since 1960, the researchers say, the environment and lifestyle on Guam has become “Westernized,” which may have something to do with the declining ALS rate. They propose an interaction of dietary factors (ingestion of cycad fruits, either directly or through eating bats that eat them) and genes probably underlies Guamanian ALS.


Researchers from Mie University in Japan say a very high incidence of ALS continues on the Kii Peninsula of that country. They believe genetic predisposition to the disease plays a role.
Variant Forms of ALS

Researchers from Portugal and the United Kingdom studied 17 patients who began their disease course with involvement of a single limb. They found that those who began with weakness in the proximal part of the limb (the part nearest the trunk) didn’t experience progression of their disease over the three to eight years that they were studied. However, those who began with weakness in a distal part of a limb (the part furthest from the trunk) were at risk for experiencing disease progression to other regions.


A group from Poland that studied 288 patients with sporadic (nonfamilial) ALS found that a slower progression than average was associated with symptoms that began in only the arms or only the legs.
Cell Biology

Understanding the biology of ALS is crucial if effective therapies are to be developed.

Researchers from the United States and Germany reported their promising study on the use of a compound called SS-31 in mice with genetic ALS. The compound enters mitochondria, the energy-producing units inside cells. The group, which included MDA-supported M. Flint Beal and Giovanni Manfredi, both at Weill Medical College of Cornell University in New York, found that mice treated with SS-31 starting at 30 days of age showed significant improvement in survival and motor performanced, as well as reduced cell loss in the spinal cord.


A group from the Institute of Neuroscience in Tokyo reported how microglia, one of the cell types in the nervous system, can be both harmful and helpful in ALS. Microglia can participate in harmful inflammatory responses, but they can also play a role in protecting nerve cells. They found that microglia have to first migrate to the site of damage of nerve cells, where they can secrete protective compounds.
Impact of Long-Term Survival

People with ALS are surviving longer than ever before, thanks largely to interventions such as assisted ventilation and nutritional support. Several groups reported on the implications of longer survival for the patient and family.

Investigators at Niigata University in Japan studied 102 people with ALS, 28 of whom used assisted ventilation and 74 of whom did not. The median survival in the ventilated group was 4.5 yeras; in the nonventilator group, it was two years.


Only one person developed cognitive dysfunction (dementia), and it was mild. This person was on assisted ventilation for 9.5 years.

The researchers concluded that cognitive function for most ventilated patients remains unaffected for a long time, and that patients are capable of changing their minds about ventilation after they begin using it.


Investigators at Tokyo Metropolitan Neurologic Hospital studied 100 ALS patients on tracheostomy-delivered ventilation and concluded that a new view of ALS should now prevail. Rather than measuring disease duration from onset to respiratory failure, it should be measured from onset to involvement of all motor functions.
Provision of means of communication for patients in the late stages of ALS should be paramount, they said. Patients should be given communication devices when they’re needed, but they should also be encouraged to examine decision making in the physician-patient-family circle. At present, the patient is less likely to be part of the decision making process in Japan than in the West.

Cognitive and Behavioral Changes

It’s well known that some people with ALS experience changes in thinking (cognition) and behavior that may be related to their situation, their brain function or both.

Investigators from Cambridge, United Kingdom, studied 15 people with ALS and dementia (severe cognitive dysfunction) and found that the pattern of behavioral and cognitive changes in this condition were different from those seen in dementia not associated with ALS. They found that ALS-related dementia is characterized by frequent delusions and hallucinations and by impaired processing of language, and they say it should be considered a separate disease entity.


A U.S. group reported its finding that some 30 percent of people with frontotemporal dementia have some motor impairment as well.


Researchers from the Forbes Norris MDA/ALS Center at California Pacific Medical Center in San Francisco evaluated cognition in 47 people with ALS and found that 23 were impaired and 24 were normal. Behavioral changes occurred in 56 percent of the cognitively impaired and 58 percent of the cognitively unimpaired patients, the most common problem being apathy. In general, however, they saw greater behavioral change in those with cognitive deficits than in those without them.
Support for Caregivers

Investigators from the United Kingdom, Denmark and Australia reported findings about caregivers.

A group from the University of Birmingham, England, reported on findings about caregivers of patients with dementia and suggested that many of these observations could also be applied to caregiving in other devastating conditions, such as ALS. The researchers identified five factors as determinants of caregivers stress: 1) the quality of the prior relationship between caregiver and care recipient; 2) direct effects on the caregiver, such as broken sleep or heavy lifting; 3) competition for the caregiver’s time, such as from work or raising children; 4) psychological strain, such as impact on self-esteem of the caregiver; and 5) social support networks.


They found helpful interventions should be directed at both the caregiver and the care recipient, individually tailored, and intensive.


Researchers from La Trobe University in Melbourne, Australia, reported the results of a survey they mailed to 74 caregivers of someone with ALS. They found there was a trend toward increasing feelings of loss as the time spent caregiving increased. The main factors were relatives not keeping in touch; difficulties in relationships with friends; and financial hardship.


Fourteen of the caregivers volunteered to be interviewed. Data from these interviewed correlated with the survey findings and provided additional insight. Caregivers said they experienced a loss of relationships through functional changes, redefinition of roles among family members and their friends, distress with the uncertainties surrounding disease progression, and a perceived need to keep their feelings to themselves.


The researchers suggest that helping a caregiver find a confidant with whom they can share feelings freely and providing connections to other caregivers may help.


Researchers from the University of Oxford in England reported that not all caregivers are comfortable seeking help. They suggest that professionals offer emotional support and practical advice.


Danish researchers described their practice of inviting four to eight families affected by ALS to participate in an intensive two-day course that deals with the medical, mental and social aspects of the disease. Participants said that meeting other families in a similar situation and taking the course with their partners were helpful.