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December
1, 2006
(updated Dec.
4, 2006)
Researchers
From Around the World
Present Findings at International
Conference on ALS
by
Margaret Wahl
Web
site: Motor
Neurone Disease Association -
International Symposium on ALS/MND
Dec.
2 Sessions
More About
ALS-Associated Genes
Some genes, and
the proteins made from them, have
been implicated in previous studies.
New findings are now shedding
light on their normal cellular
roles and what may go wrong when
they malfunction.
-
A
group from Tokyo presented findings
about the gene for VAPB, which,
when mutated, can cause ALS.
They reported that a mutation
in the VAPB gene can make the
VAPB protein much less soluble
and cause it to end up in the
wrong cellular compartment.
-
A
group from Tokai University
in Kanagawa, Japan, reported
findings about the gene for
the alsin protein. This gene,
when mutated, causes a juvenile-onset
form of ALS. The group reported
that the normal function of
alsin is probably to participate
in development of nerve fibers
(axons) in immature nerve cells
and to play a role in moving
compounds to the cell membrane
in mature nerve cells. They
also reported that a protein
called Rac1 activates alsin.
-
Investigators
associated with the U.S. National
Institutes of Health (NIH) in
Bethesda, Md., and the Packard
Center for ALS Research at Johns
Hopkins University in Baltimore,
are conducting a genetic screen
of 1,000 people with and without
ALS. Bryan Traynor and John
Hardy at NIH are leading this
study, which is similar to but
separate from the screen MDA
is supporting through the Translational
Genomics Research Institute
(see Nov. 30 sessions). Specific
results are not yet available.
Major Medical Center Care
Versus Community Care
Investigators have
been collecting data on ALS care
in major medical centers for several
years and have recently been collecting
data from patients being seen
outside such centers. They’re
comparing findings from the two
groups.
-
An MDA-supported group reported
on comparisons between data
from the ALS CARE Database and
the ALS Connection. The ALS
CARE Database is paper-based
and targets ALS patients at
major medical centers; the ALS
Connection is Web-based and
targets ALS patients not being
seen at major medical
centers.
The
group included Robert Miller,
director of the Forbes Norris
MDA/ALS Center at Pacific National
Medical Center in San Francisco,
who received MDA funding to
develop the ALS Connection;
Benjamin Brooks, director of
the MDA/ALS Center at the University
of Wisconsin-Madison; and Hiroshi
Mitsumoto, co-director of the
Eleanor and Lou Gehrig MDA/ALS
Center at Columbia University
in New York.
The researchers reported that,
compared with ALS CARE registrants,
patients who registered with
the ALS Connection experienced
a greater impact on their lives
from ALS; were generally less
satisfied with their care; had
a less satisfactory experience
learning about their diagnosis;
and had less access to symptom-relieving
therapy.
New Thoughts
About Glutamate Clearance
For many years,
ALS investigators have proposed
that excess glutamate, a normal
carrier of signals in the nervous
system, can be toxic to nerve
cells. Some have emphasized that
the clearance of glutamate away
from the cells is deficient in
people with ALS.
-
Researchers
from Birmingham, England, reported
results of their search for
proteins that interact with
EAAT2, a compound that helps
clear potentially toxic glutamate
from the area around nerve cells.
They discovered three proteins
that interact with EAAT2 and
said the next challenge is to
find out how these interactions
influence EAAT2 and whether
changes in any of these proteins
have relevance to ALS.
The Immune
System In ALS
For several years,
scientists have implicated inflammation,
an important part of the immune
response, as a probable contributor
to ALS. But there’s also
evidence to show that the immune
system can be a positive influence
in this disease.
-
U.S.
researchers from the Cleveland
(Ohio) Clinic reported that
artificially activated microglia,
immune system cells in the spinal
cord and brain, initially help
motor nerve cells to function
in mice with genetic ALS, but
that this is transient and gives
way to harmful effects, with
loss of nerve cells and shorter
survival times.
-
A
group that included Stan Appel,
director of the MDA/ALS Center
at Methodist Neurological Institute
in Houston, reported that microglia
in mice with genetic ALS were
more toxic than normal microglia,
and that they’re even
more harmful when immune system
cells in the blood are artificially
eliminated. They said their
results suggest that blood immune
system cells might be manipulated
to enhance their neuroprotective
activity.
-
Three
proteins, known as IL-1RN, FPRL1
and CHI3L1, are found at higher
levels in people with ALS than
in people without ALS, according
to a group that included Robert
Miller, director of the Forbes
Norris MDA/ALS Center in San
Francisco. Blood cells from
people with ALS are “committed
to a pro-inflammatory program,”
the group reported, noting that
this distinct profile might
be useful for diagnosing ALS
at an earlier than usual stage.
Respiratory
Care Advances
Weakening of the
diaphragm and other respiratory
muscles and loss of the ability
to breathe are the most serious
consequences of ALS-related neurologic
dysfunction. In recent years,
noninvasive and invasive methods
of assisted ventilation have prolonged
life in ALS, but doctors continue
to refine these.
-
A
test of respiratory function
that measures “maximal
inspiratory pressure”
(MIP) appears to be a more sensitive
indicator of respiratory dysfunction
in ALS than forced vital capacity
(FVC), reported a group that
included Stan Appel, director
of the MDA/ALS Center at Methodist
Neurological Institute in Houston.
They said MIP results may be
abnormal before FVC results
show abnormalities, and this
may imply that ventilation should
be started earlier in some patients.
-
Robert Sufit, who directs the
MDA clinic at Northwestern Memorial
Hospital in Chicago, and colleagues,
reported that ALS patients appear
to benefit from respiratory
monitoring at a minimum of every
three months and more frequently
if symptoms appear.
-
Stimulation
of the phrenic nerve, which
controls the diaphragm, has
been a controversial technique
in ALS. But Raymond Onders and
colleagues at Case Western Reserve
University in Cleveland, Ohio,
reported that they tested the
technique on eight people with
ALS and found it does have benefits.
There were no deaths in the
group, and no one needed a tracheostomy.
Monthly decline in respiratory
function, as defined by changes
in forced vital capacity, slowed.
-
Jeffrey
Rosenfeld, who directs the MDA/ALS
Center at Carolinas Medical
Center in Charlotte, N.C., also
tested phrenic nerve stimulation
and found it beneficial in two
out of the three ALS patients
in this small study. Decline
in forced vital capacity stabilized,
use of noninvasive ventilation
decreased, and the patients
assessed their functional ability
as greatly increased.
Dec.
1 Sessions
More On
Genetic Factors In ALS
The role of genetic
factors in ALS, even when there’s
no apparent family history of
the disease, is undisputed. However,
identifying those factors is an
ongoing challenge.
-
A
U.S. group at Northwestern University
in Chicago presented its findings
that the gene for angiogenin
is a modifier of ALS, and that
a certain variant of the gene
appears to lower the age at
which ALS develops. This group
studied a large, North American
population of some 2,000 ALS-affected
and unaffected subjects.
Neurotrophic
Factors As Therapeutic Agents
Neurotrophic (nerve-nourishing)
factors (proteins) and the genes
for them have been considered
as potential therapeutic agents
in ALS for many years now, and
a few of the proteins have been
tested in clinical trials in people
with ALS. Unfortunately, they
have not shown benefit. Researchers
continue to expand the selection
of potential neurotrophic factors
to be tested and the strategies
used to deliver them to the nervous
system.
-
Two
Japanese research teams reported
success using hepatocyte growth
factor (HGF) in rodent models
of ALS.
-
A
U.S. group from Columbus (Ohio)
Children’s Research Institute
and Genzyme (Cambridge, Mass.)
reported that injecting genes
for insulin-like growth factor
1 (IGF1) directly into the part
of the brain called the cerebellum
in ALS-affected mice caused
the IGF1 protein to be produced
in the brain and spinal cord,
promoted survival of motor nerve
cells, improved motor performance,
and extended survival.
Limitations
of Mice As ALS Models
Since the causes
of sporadic ALS aren’t known,
the best models that scientists
have in which to study ALS and
test new treatments are mice and
rats bred to develop genetic forms
of the disease. These mice have
their limitations in predicting
the responses of humans with sporadic
ALS to new treatments.
-
Scientists
at the ALS Therapy Development
Foundation in Cambridge, Mass.,
retested compounds that had
previously shown a survival
benefit in ALS-affected mice,
but this time, they kept exquisitely
tight controls on other variables.
They concluded that, unfortunately,
many of the previously measured
benefits were probably the result
of “noise” (assessment
of variables other than the
ones they thought they were
measuring), rather than effects
of the test compound.
-
MDA
grantee Denise Figlewicz (until
recently at the University of
Michigan in Ann Arbor and now
director of the ALS Society
of Canada in Toronto), and Terry
Heiman-Patterson, director of
the MDA/ALS Center of Hope at
Drexel University in Philadelphia,
were part of a research group
that reported additional data
about ALS-affected mice. This
group found that when the ALS-causing
defect -- a mutated SOD1 gene
-- was bred into mice with different
genetic backgrounds that had
nothing to do with SOD1, the
nature of the genetic background
influenced survival time. They
also noted that, in some strains
of mice, ALS-affected females
lived longer than males; but
in other strains, this wasn’t
the case.
Improving
Clinical Trials
It’s now clear
that ALS is a heterogeneous disease,
and it’s unlikely that any
single treatment will work for
all patients. But at this time,
it’s hard to know which
treatments will work for which
patients. Some researchers are
trying to overcome this problem
by altering study designs.
-
Findings
from the Forbes Norris MDA/ALS
Research Center at California
Pacific Medical Center in San
Francisco suggest that a subset
of participants in a trial who
can be classified as “responders”
to a treatment might be identified
by measuring a decrease in the
slope of their loss of function.
Their report suggested that
participants who have a one-
to two-unit decline in their
ALS Functional Rating Scale
slope might form the basis of
smaller clinical trials that
might be more sensitive and
efficient than current trials.
Palliative
and End-of-Life Care
Although the goal
of research organizations and
families is to cure ALS, in the
meantime, it’s important
to palliate (relieve) symptoms
and support families through the
last stages of the disease.
-
A
group from Rochester, United
Kingdom, reported that ALS should
now be viewed as a chronic disease,
but one that remains ultimately
fatal. They noted that ventilation
and nutritional (gastrostomy
tube) support have extended
life, changing the role of palliative
care in this disease, but that
the need for end-of-life planning
shouldn’t be neglected.
-
A
group from the MDA/ALS Center
at Carolinas Medical Center
in Charlotte, N.C., reported
that the anti-spasticity drug
baclofen can be delivered directly
into the spinal fluid via a
pump placed in the abdomen,
and that this form of delivery
avoids the side effects of oral
medication. They studied 20
patients with ALS who couldn’t
tolerate oral medication because
of its sedative effects. The
patients were able to reduce
or eliminate their oral medication
once they were on the baclofen
pump, and there were no surgical
complications.
Telling
One’s Story
It’s always
been common for people in stressful
situations to record their thoughts
in diaries, but nowadays, the
Internet has made it possible
for such thoughts to be shared
with thousands of other people.
This kind of sharing, as well
as just talking, seems to be helpful.
-
A
British group reported their
study of 64 narratives written
by people with ALS and posted
on the Internet, seeking to
determine what people with ALS
write about; why they do it;
and whether these writings benefit
anyone.
They
found that people with ALS regularly
update their readers on their
condition, often including management
tips; stress what they can still
do rather than what they can’t
do; discuss changes in relationships,
especially with partners and
spouses; and report their use
of alternative therapies.
The
motivation for the writing seemed
to be largely to lessen the
burden on others in similar
situations, providing them with
awarness, resources and inspiration.
Readers
of the narratives reported being
comforted, enlightened and supported,
and feeling less isolated.
-
Australian
researchers studied and reported
on 25 people with ALS for whom
relating the story of their
ALS diagnosis seemed to have
a beneficial effect. The investigators
likened the diagnosis experience
of these patients to that of
people with post-traumatic stress
disorder, noting that many continued
to relive the experience in
dreams and in their daily lives
months after the event. They
found that receiving an ALS
diagnosis is itself a “traumatic
stressor.” However, people
appreciated the debriefing opportunity
that telling their story offered.
The researchers recommend this
kind of support.
Nov. 30
Sessions
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.
-
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.
-
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.
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