Update on ALS research Prof. Ole-Bjørn Tysnes Dept of Neurology Haukeland University Hospital

What is ALS? Clinical characteristicsClinical characteristics Pathological findingsPathological findings Genetics in ALSGenetics in ALS

Clinical characteristics May start with symptoms like speech or swallowing difficulties (bulbar ALS)May start with symptoms like speech or swallowing difficulties (bulbar ALS) Most frequently start as progressive weakness in a limb (classic ALS)Most frequently start as progressive weakness in a limb (classic ALS) Fasciculations frequently apparentFasciculations frequently apparent Slightly more frequent in men than womenSlightly more frequent in men than women Annual incidence 2/ per yearAnnual incidence 2/ per year

EMG essential to ensure the diagnosisEMG essential to ensure the diagnosis Important differential diagnoses must always be consideredImportant differential diagnoses must always be considered –Cervical radiculomyelopathy –Post polio syndrome –Motor neuropathies Conditions with gammopathiesConditions with gammopathies Diabetic amyotrophyDiabetic amyotrophy –Myasthenia gravis

ALS is a serious and gradually progressive diseaseALS is a serious and gradually progressive disease Survival time may however vary considerablySurvival time may however vary considerably Involve all muscles of the body with timeInvolve all muscles of the body with time Eye muscles are only affected very lateEye muscles are only affected very late Mental symptoms may occur during the course of the diseaseMental symptoms may occur during the course of the disease

Pathological characteristics Loss of motor neurons in the spinal cordLoss of motor neurons in the spinal cord Diffuse sclerosis of the spinal cordDiffuse sclerosis of the spinal cord

Genetics in ALS Most ALS cases (more than 90%) are sporadicMost ALS cases (more than 90%) are sporadic If inherited (less than 10%) almost all cases are autosominal dominant (present in every generation)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)20% of the inherited cases are related to mutations in SOD (superoxide dismutase) Mutations other than SOD are very rare in ALSMutations other than SOD are very rare in ALS

On this background: Where do we stand in ALS research? Epidemiologic researchEpidemiologic research Genetic researchGenetic research Disease modifying treatment in ALSDisease modifying treatment in ALS –In ALS models –In patients (treatment trials) Stem cellsStem cells ALS managementALS management

Update on epidemiologic research Increase in ALS?Increase in ALS? Environmental factors?Environmental factors? Increased risk in Gulf war veterans and professional football players?Increased risk in Gulf war veterans and professional football players? Mental symptoms in ALS?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/ /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 ALSMutations related to ALS Diversity in the impact of SOD mutationsDiversity in the impact of SOD mutations Genetic variants with ALS and dementiaGenetic 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

ALS Bulb. ALSSpinal ALSSpinal ALSFTD Are ALS and Frontotemporal dementia linked? Norwegian ALS/FTD family

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 modelsIn ALS animal models –By the use of drugs –By genetic modelling In patients (treatment trials)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 modelsALS animal models Humans: Latest news from EFNSHumans: 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 2007Survival

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 The price for intrathecal stem cell therapy is $ 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 performedVery much ALS research is performed No breakthrough has been done on treatmentNo breakthrough has been done on treatment Extensive research on basic pathology in ALS may open up new possibilitiesExtensive 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 diseaseClinical research on ALS management give better possibilities of dealing with problems that occur during the course of the disease