Update on ALS research
Prof. Ole-Bjørn Tysnes
Dept of Neurology
Haukeland University Hospital
What is ALS?
• Clinical characteristics
• Pathological findings
• Genetics in ALS
Clinical characteristics
• May start with symptoms like speech or
swallowing difficulties (bulbar ALS)
• Most frequently start as progressive
weakness in a limb (classic ALS)
• Fasciculations frequently apparent
• Slightly more frequent in men than women
• Annual incidence 2/100.000 per year
• EMG essential to ensure the diagnosis
• Important differential diagnoses must
always be considered
– Cervical radiculomyelopathy
– Post polio syndrome
– Motor neuropathies
• Conditions with gammopathies
• Diabetic amyotrophy
– Myasthenia gravis
• ALS is a serious and
gradually progressive
disease
• Survival time may
however vary
considerably
• Involve all muscles of
the body with time
• Eye muscles are only
affected very late
• Mental symptoms may
occur during the course
of the disease
Pathological characteristics
• Loss of motor neurons in the spinal cord
• Diffuse sclerosis of the spinal cord
Genetics in ALS
• Most ALS cases (more than 90%) are
sporadic
• If inherited (less than 10%) almost all cases
are autosominal dominant (present in every
generation)
• 20% of the inherited cases are related to
mutations in SOD (superoxide dismutase)
• Mutations other than SOD are very rare in
ALS
On this background: Where do
we stand in ALS research?
• Epidemiologic research
• Genetic research
• Disease modifying treatment in ALS
– In ALS models
– In patients (treatment trials)
• Stem cells
• ALS management
Update on epidemiologic research
• Increase in ALS?
• Environmental factors?
• Increased risk in Gulf war veterans and
professional football players?
• Mental symptoms in ALS?
Increase in incidence of
ALS?
Seljeseth et al 2000
Traynor el al 2007
Stable incidence in Ireland
during the last 7 years
Annual incidence 2.5/100.000/Y
ALS slightly more frequent in men
than women
Decrease in ALS incidence in
the oldest age groups
Environmental risk factors in ALS?
OB Tysnes, ACNR, 2004
Chio et al, Brain, 2005:
Severely increased risk of ALS among Italian professional
football players
Wicks et al, Amyotrophic Lateral Sclerosis, 2007:
Three soccer playing friends with simultaneous amyotrophic
lateral sclerosis
Armon 2007, J Neurol Sci
Most likely not increased
risk of ALS in football
players
Mental tests that are independent of motor perfomance
Conclusion:
50% of ALS patients have significant but small mental deficits
15% of ALS patients fullfil criteria of Frontotemporal dementia
Update on genetic research
• Mutations related to ALS
• Diversity in the impact of SOD mutations
• Genetic variants with ALS and dementia
Strange et al, PNAS, 2007
More than 100 mutations
in SOD1 can cause ALS
Loss of Zn molecules in
SOD destabilises the
molecule
This will with time lead
to aggregation of SOD1
molecules
Such aggregation may
preceede neuronal death
Peter Andersen (Umeå):
Different SOD mutations give variable phenotype in ALS
Age of onset vary considerable within the same mutation
Disease duration short in som familial ALS and long in others
Are ALS and Frontotemporal dementia linked?
Norwegian ALS/FTD family
ALS
Bulb. ALS
Spinal ALS
Spinal ALS
FTD
Spina et al, Neurology 2007
FTD and ALS may be linked to
mutations in progranuline, but
other genetic causes are likely
to occur
Update on disease modifying
treatment
• In ALS animal models
– By the use of drugs
– By genetic modelling
• In patients (treatment trials)
– Oral drugs
– Infusion therapies
Jung et al, Neurosci Lett, 2001
Antioxidant therapy (EUK-8 and EUK-134) increase
survival in SOD mice.
Pompl et al, FASEB journal 2003:
Cox2 inhibition delays progression of disease in SOD Mice
Ermilova et al, Neurosci lett 2005
Effects of Zn in the diet on survival of SOD
transgenic mice.
Marden et al, J Clin Invest, 2007
Genetic treatment of SOD mice by inhibition of
NAPDH oxidases Nox 1 and Nox 2 (knock outs)
Problem: Lethal eye infection in cases of the NOX 2 knock outs
Use of stem cells: Charlatans or
any evidence of effect?
• ALS animal models
• Humans: Latest news from EFNS
Suzuki et al, PNOS1 2007:
Implanted GDNF secreting human progenitor cells make
motor neurons survive, but do not prolong survival in SOD mice
Motor neuron
survival
Suzuki et al
2007
Survival
Habisch et al, J Neural Trans, 2007
Injection of neural stem cells in the cisterna magna did not
prolong survival of SOD mice
Question from the authors: Too few cells transplanted?
Miller et al, Neurology, 2007
No effect of antiapoptotic treatment (TCH346) in ALS
Giordano et al, Cell Physiol, 2007
No effect of any stem cell therapy to day
Several serious adverse events, even lethal. Most frequent are
infections and allergic reactions
EFNS August 2007
- The price for intrathecal stem cell therapy is $ 50.000
and its currently given in Russia and China
- They claim 6 months increased survival
- No data on efficacy has been provided
Conclusion:
- Current clinical stem cell treatment in ALS is run by charlatans
ALS management
Neppelberg et al, Eur J Neurol, 2007
Radiotherapy significantly reduces sialorrhea in ALS
Neppelberg et al, Eur J Neurol, 2007
Patient are satisfied with the effect of radiotherapy on
sialorrhea.
Is training bad for ALS patients?
Liebetanz et al, J Neurol Sci, 2004:
No differences in strength evolotion or survival in SOD mice
between sedentary, control and actively trained mice. A tendency
that the trained group survived longer
Bello-Haas et al, Neurology, 2007
ALS patients in careful training had better ALS Functional Rating
Score at the end of the study
Conclusions
• Very much ALS research is performed
• No breakthrough has been done on treatment
• Extensive research on basic pathology in
ALS may open up new possibilities
• Clinical research on ALS management give
better possibilities of dealing with problems
that occur during the course of the disease