Update on ALS researchUpdate on ALS research

Prof. Ole-Bjørn TysnesProf. Ole-Bjørn Tysnes

Dept of NeurologyDept of Neurology

Haukeland University HospitalHaukeland University Hospital

What is ALS?What is ALS?

• Clinical characteristicsClinical characteristics

• Pathological findingsPathological findings

• Genetics in ALSGenetics in ALS

Clinical characteristicsClinical characteristics

• May start with symptoms like speech or May start with symptoms like speech or swallowing difficulties (bulbar ALS)swallowing difficulties (bulbar ALS)

• Most frequently start as progressive Most frequently start as progressive weakness in a limb (classic ALS)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 2/100.000 per yearAnnual incidence 2/100.000 per year

• EMG essential to ensure the diagnosisEMG essential to ensure the diagnosis

• Important differential diagnoses must always be Important differential diagnoses must always be consideredconsidered– Cervical radiculomyelopathyCervical radiculomyelopathy– Post polio syndromePost polio syndrome– Motor neuropathiesMotor neuropathies

• Conditions with gammopathiesConditions with gammopathies• Diabetic amyotrophyDiabetic amyotrophy

– Myasthenia gravisMyasthenia gravis

• ALS is a serious and gradually ALS is a serious and gradually progressive diseaseprogressive disease

• Survival time may however vary Survival time may however vary considerablyconsiderably

• Involve all muscles of the body Involve all muscles of the body with timewith time

• Eye muscles are only affected Eye muscles are only affected very latevery late

• Mental symptoms may occur Mental symptoms may occur during the course of the diseaseduring the course of the disease

Pathological characteristicsPathological 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 ALSGenetics 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 If inherited (less than 10%) almost all cases are autosominal dominant (present in every autosominal dominant (present in every generation)generation)

• 20% of the inherited cases are related to 20% of the inherited cases are related to mutations in SOD (superoxide dismutase)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 On this background: Where do we stand in ALS research?we stand in ALS research?

• Epidemiologic researchEpidemiologic research

• Genetic researchGenetic research

• Disease modifying treatment in ALSDisease modifying treatment in ALS– In ALS modelsIn ALS models– In patients (treatment trials)In patients (treatment trials)

• Stem cellsStem cells

• ALS managementALS management

Update on epidemiologic researchUpdate on epidemiologic research

• Increase in ALS?Increase in ALS?

• Environmental factors?Environmental factors?

• Increased risk in Gulf war veterans and Increased risk in Gulf war veterans and professional football players?professional football players?

• Mental symptoms in ALS?Mental symptoms in ALS?

Increase in incidence ofIncrease in incidence ofALS?ALS?

Seljeseth et al 2000Seljeseth et al 2000

Traynor el al 2007Traynor el al 2007

Stable incidence in IrelandStable incidence in Irelandduring the last 7 yearsduring the last 7 yearsAnnual incidence 2.5/100.000/YAnnual incidence 2.5/100.000/Y

ALS slightly more frequent in menALS slightly more frequent in menthan womenthan women

Decrease in ALS incidence inDecrease in ALS incidence inthe oldest age groupsthe oldest age groups

Environmental risk factors in ALS?Environmental risk factors in ALS?

OB Tysnes, ACNR, 2004OB Tysnes, ACNR, 2004

Chio et al, Brain, 2005:Chio et al, Brain, 2005:Severely increased risk of ALS among Italian professionalSeverely increased risk of ALS among Italian professionalfootball playersfootball players

Wicks et al, Amyotrophic Lateral Sclerosis, 2007:Wicks et al, Amyotrophic Lateral Sclerosis, 2007:Three soccer playing friends with simultaneous amyotrophicThree soccer playing friends with simultaneous amyotrophiclateral sclerosislateral sclerosis

Armon 2007, J Neurol SciArmon 2007, J Neurol Sci

Most likely not increasedMost likely not increasedrisk of ALS in footballrisk of ALS in footballplayersplayers

Mental tests that are independent of motor perfomanceMental tests that are independent of motor perfomance

Conclusion: Conclusion: 50% of ALS patients have significant but small mental deficits50% of ALS patients have significant but small mental deficits15% of ALS patients fullfil criteria of Frontotemporal dementia15% of ALS patients fullfil criteria of Frontotemporal dementia

Update on genetic researchUpdate 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, 2007Strange et al, PNAS, 2007

More than 100 mutationsMore than 100 mutationsin SOD1 can cause ALSin SOD1 can cause ALS

Loss of Zn molecules inLoss of Zn molecules inSOD destabilises the SOD destabilises the moleculemolecule

This will with time leadThis will with time leadto aggregation of SOD1to aggregation of SOD1moleculesmolecules

Such aggregation maySuch aggregation maypreceede neuronal deathpreceede neuronal death

Peter Andersen (Umeå):Peter Andersen (Umeå):

Different SOD mutations give variable phenotype in ALSDifferent SOD mutations give variable phenotype in ALSAge of onset vary considerable within the same mutationAge of onset vary considerable within the same mutationDisease duration short in som familial ALS and long in othersDisease duration short in som familial ALS and long in others

ALS

Bulb. ALS Spinal ALS Spinal ALS FTD

Are ALS and Frontotemporal dementia linked?Are ALS and Frontotemporal dementia linked?

Norwegian ALS/FTD familyNorwegian ALS/FTD family

Spina et al, Neurology 2007Spina et al, Neurology 2007

FTD and ALS may be linked toFTD and ALS may be linked tomutations in progranuline, butmutations in progranuline, butother genetic causes are likelyother genetic causes are likelyto occurto occur

Update on disease modifying Update on disease modifying treatmenttreatment

• In ALS animal modelsIn ALS animal models– By the use of drugsBy the use of drugs– By genetic modellingBy genetic modelling

• In patients (treatment trials)In patients (treatment trials)– Oral drugsOral drugs– Infusion therapiesInfusion therapies

Jung et al, Neurosci Lett, 2001Jung et al, Neurosci Lett, 2001

Antioxidant therapy (EUK-8 and EUK-134) increaseAntioxidant therapy (EUK-8 and EUK-134) increasesurvival in SOD mice.survival in SOD mice.

Pompl et al, FASEB journal 2003: Pompl et al, FASEB journal 2003:

Cox2 inhibition delays progression of disease in SOD MiceCox2 inhibition delays progression of disease in SOD Mice

Ermilova et al, Neurosci lett 2005Ermilova et al, Neurosci lett 2005

Effects of Zn in the diet on survival of SODEffects of Zn in the diet on survival of SODtransgenic mice.transgenic mice.

Marden et al, J Clin Invest, 2007Marden et al, J Clin Invest, 2007

Genetic treatment of SOD mice by inhibition ofGenetic treatment of SOD mice by inhibition ofNAPDH oxidases Nox 1 and Nox 2 (knock outs)NAPDH oxidases Nox 1 and Nox 2 (knock outs)

Problem: Lethal eye infection in cases of the NOX 2 knock outsProblem: Lethal eye infection in cases of the NOX 2 knock outs

Use of stem cells: Charlatans or Use of stem cells: Charlatans or any evidence of effect?any evidence of effect?

• ALS animal modelsALS animal models

• Humans: Latest news from EFNSHumans: Latest news from EFNS

Suzuki et al, PNOS1 2007:Suzuki et al, PNOS1 2007:

Implanted GDNF secreting human progenitor cells makeImplanted GDNF secreting human progenitor cells makemotor neurons survive, but do not prolong survival in SOD micemotor neurons survive, but do not prolong survival in SOD mice

Motor neuronMotor neuronsurvivalsurvival

Suzuki et alSuzuki et al20072007

SurvivalSurvival

Habisch et al, J Neural Trans, 2007Habisch et al, J Neural Trans, 2007

Injection of neural stem cells in the cisterna magna did not Injection of neural stem cells in the cisterna magna did not prolong survival of SOD miceprolong survival of SOD mice

Question from the authors: Too few cells transplanted?Question from the authors: Too few cells transplanted?

Miller et al, Neurology, 2007Miller et al, Neurology, 2007

No effect of antiapoptotic treatment (TCH346) in ALSNo effect of antiapoptotic treatment (TCH346) in ALS

Giordano et al, Cell Physiol, 2007Giordano et al, Cell Physiol, 2007

No effect of any stem cell therapy to dayNo effect of any stem cell therapy to daySeveral serious adverse events, even lethal. Most frequent areSeveral serious adverse events, even lethal. Most frequent areinfections and allergic reactionsinfections and allergic reactions

EFNS August 2007EFNS August 2007

- The price for intrathecal stem cell therapy is $ 50.000 - The price for intrathecal stem cell therapy is $ 50.000 and its currently given in Russia and Chinaand its currently given in Russia and China- They claim 6 months increased survival- They claim 6 months increased survival- No data on efficacy has been provided- No data on efficacy has been provided

Conclusion:Conclusion:- Current clinical stem cell treatment in ALS is run by charlatans- Current clinical stem cell treatment in ALS is run by charlatans

ALS managementALS management

Neppelberg et al, Eur J Neurol, 2007Neppelberg et al, Eur J Neurol, 2007

Radiotherapy significantly reduces sialorrhea in ALSRadiotherapy significantly reduces sialorrhea in ALS

Neppelberg et al, Eur J Neurol, 2007Neppelberg et al, Eur J Neurol, 2007

Patient are satisfied with the effect of radiotherapy onPatient are satisfied with the effect of radiotherapy onsialorrhea.sialorrhea.

Is training bad for ALS patients?Is training bad for ALS patients?

Liebetanz et al, J Neurol Sci, 2004:Liebetanz et al, J Neurol Sci, 2004:No differences in strength evolotion or survival in SOD miceNo differences in strength evolotion or survival in SOD micebetween sedentary, control and actively trained mice. A tendencybetween sedentary, control and actively trained mice. A tendencythat the trained group survived longerthat the trained group survived longer

Bello-Haas et al, Neurology, 2007Bello-Haas et al, Neurology, 2007

ALS patients in careful training had better ALS Functional RatingALS patients in careful training had better ALS Functional RatingScore at the end of the studyScore at the end of the study

ConclusionsConclusions

• 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 Extensive research on basic pathology in ALS may open up new possibilitiesALS may open up new possibilities

• Clinical research on ALS management give Clinical research on ALS management give better possibilities of dealing with problems better possibilities of dealing with problems that occur during the course of the diseasethat occur during the course of the disease