alsreport_2005

Amyotrophic Lateral SclerosisA report on the state of research into the cause, cure, and prevention of ALS

June 2005

Presented to the Department of Public Health, State of Massachusetts By the ALS Therapy Development Foundation

Contributors: Jennifer ClarkDoctoral Candidate, Department of the History of Science, Harvard University

Colin Pritchard, Ph.D.Professor Emeritus, School of Medicine, University of Southampton Research Professor, Psychiatric Social Work, Institute of Health and Community Studies, Bournemouth University

Sanjay Sunak, B.Sc.Research Assistant, Mental Health Group, School of Medicine, University of Southampton

Funding provided by the Massachusetts Department of Public Health

CONTENTS: EpidemiologyandEtiologyofALS ExecutiveSummary FullReport AppendixA:Methodology

ClinicalTrialsinALS FullReport AppendixA:ListofallClinicalTrialsinALS AppendixB:IndividualClinicalTrialSummaries

CurrentResearchTopicsinALS FullReport AppendixA:BiomarkersinALS AppendixB:InVitroModelsofALS

SelectedAdditionalResourcesonALS

TheEpidemiologyandEtiologyofALSAnExecutiveSummary June2005 AreporttotheDepartmentofPublicHealth,StateofMassachusetts onbehalfoftheALSTherapyDevelopmentFoundation. JenniferClarkDoctoralCandidate,DepartmentoftheHistoryofScience,HarvardUniversity

EpidemiologyofALS

Page1of15

THEEPIDEMIOLOGYANDETIOLOGYOFALS AnExecutiveSummary1

Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurological disorder that causes weakness, atrophy, paralysis, andeventuallyrespiratoryfailureduetothe selective degeneration of neurons

biological, genetic, environmental, and socialfactorsthatimpactindividualsriskof developingALS. Thisreviewprovidesaconciseoverviewof Colin Pritchard & Sanjay Sunaks extensive technical report on epidemiological and publichealthresearchonALS.3Thisreview is primarily intended for a policy and advocacyaudienceandaddressesthemajor findings and key arguments contained in thatreport. In brief, Pritchard & Sunak provide compelling evidence that the incidence of ALS is increasing in the United States and throughout most of the Western world. Based on both the published

responsible for voluntary movement. Since its discovery in 1874, ALS has remained a medical mystery researchers remain unable to identify any clear cause, cure, or effective treatment for the disease.2

Throughout the history of research on the disease, epidemiological and public health researchapproacheshaveplayedakeyrole in informing policy and advancing

knowledge on the disease. Epidemiological studies have helped change early

perceptions of ALS as an extremely rare disease, and as a result the disease has become an increasing focus of policy interventions and research funding.

epidemiological literature on ALS and original research, Pritchard & Sunak demonstrate that these increases follow distinct patterns with ALS incidence increasing the most rapidly in women and

Epidemiological and public health research perspectives have also provided important clues to the etiology of ALS, and to the

EpidemiologyofALS

Page2of15

inyoungeragebracketsthanthoseinwhich have historically had the highest incidence of ALS. Some researchers have attributed apparent increases in the incidence of ALS to increased longevity among the general population, but Pritchard & Sunak argue that the observed patterns of increased incidence are at odds with this hypothesis. Convinced that increases in ALS incidence cannot be ascribed to changing age demographics alone, Pritchard & Sunak conduct an extensive review of the literature on biological, genetic,

Pritchard&Sunakconcludetheirreviewby highlighting the importance of holistic public health and epidemiological

approaches to future research on the disease. 1.BackgroundonALS AlthoughALSwasfirstidentifiedin1874,it isunclearwhetherthediseaseisarelatively modern affliction or one that has affected people throughout history. A number of historical documents describe diseases involving paralysis and atrophy, but given the wide range of conditions that could be described by these criteria it is difficult to determine whether or not these references areevidenceofALS.4

environmental and social factors that may have played a role in ALS changing patterns of incidence over the past several decades. Pritchard & Sunak argue that no

single research discipline can convincingly explain the changing patterns of ALS incidence. Instead, ALS appears to be influencedbyacomplexarrayofbiosocio environmental dynamics; Pritchard & Sunak implicate a wide array of social and environmental changes over the past several decades in the increased incidence (and, hence, the underlying etiology) of ALS.Ifanything,Pritchard&Sunakimply thatthecontinuedfocusonseekingasingle, simpleexplanationforboththeetiologyand changing epidemiology prevents a more complex understanding of the disease. American researchers frequently use the term ALS to refer to not only classic ALS (degenerationoftheloweranduppermotor neurons), but also to several variant motor neuron syndromes, including progressive muscular atrophy (PMA, disease affecting primarily the lower motor neurons), primarily lateral sclerosis (PLS, disease affecting primarily the upper motor neurons), and progressive bulbar palsy (PBP, disease affecting the brainstem lower motor neurons controlling the facial, tongue, and pharyngeal muscles.) In the

EpidemiologyofALS

Page3of15

United Kingdom and elsewhere, the term motor neuron disease is more frequently used to describe these four conditions.5 Because ALS is the most common motor neurondisease,andbecausePMA,PLS,and PBP more often than not are rediagnosed as ALS as the disease progresses and other groups of motor neurons become affected, both this review and research in general focusesprimarilyonclassicALS. Roughly 90% of all ALS cases appear to occur at random (termed sporadic ALS), while10%arefamilialinnature.Generally, ALS is perceived as affecting men more frequently than women (a ratio of roughly 1.4:1.0),althoughintheearlyyearsafterthe diseases discovery women were perceived to be at higher risk for the disease.6 Epidemiologicalstudiessettheincidenceof ALSatbetween10and30casespermillion population and the prevalence at between 30 and 50 cases per million population. Clinical and laboratory research

Although a number of hypotheses have been proposed over the years, there is still little conclusive data on the causes, contributing factors, or possible cure of ALS. Key findings of the past six decades have included the discovery of unusually highincidenceofALSonGuamandtheKii peninsulainJapan,thediscoveryofaseries of mutations in Cu/Zn superoxide

dismutase1(SOD1)responsibleforfamilial ALS, and the identification of glutamate excitotoxicity as a possible target for therapeuticintervention(viathemarginally successoftheantiglutamateagentRiluzole inslowingdiseaseprogression.)Theseand a wide range of more recent research findingshave provided clues,butso far no major breakthroughs, in unlocking the mystery of ALS.8 While current laboratory researchonALSwillbediscussedingreater detail in a later report, this summary focuses primarily on the public role of

epidemiological

and

health

approaches in understanding both the etiology of ALS and the implications of laboratory and clinical research on the disease.

descriptions of ALS have tended to favor the higher end of these estimates; ALS is commonly described as affecting between 5,000 and 8,000 new people per year in the U.S., with a prevalence of 30,000 cases nationwide.7

EpidemiologyofALS

Page4of15

2.EpidemiologyofALS Because ALS is perceived as a primarily sporadic disease, changes in the incidence ofALShavetraditionallybeendismissedby researchers as an artifact of increased longevity. This hypothesis, known as the Gompertzian hypothesis after the early 19th centurymathematicianonwhoseworkitis based, holds that as acute, earlyonset diseases have declined and human

which the incidence of ALS is markedly higherthaninthegeneral population.The earliest such clusters were those found on theislandofGuamandtheKiipeninsulaof Japan.Inbothcases,ratesofALSincidence werebetween50and100timesgreaterthan average, although it was not clear that the Guamanian and Kii manifestations of the disease were necessarily classic ALS Guamanians and members of the Kii peninsula appeared to suffer from a range of neurological disorders and symptoms (oftenreferredtoastheALS/Parkinsonism dementia complex or ALS/PDC) in near epidemic patterns. A number of key researchstudieshavefocusedonGuamand the Kii peninsula in an attempt to understand both the nature of the clinical syndrome (whether it is the same ALS as observed in the rest of the world) and the reason for the increased incidence, with mixed results.9 Since the 1960s, the incidence of neurological disorders on Guam and the Kii peninsula have been steadily declining with increasing to

longevity has increased, the incidence of a range of lateonset sporadic and genetic diseases has increased as a result of a greater number of people reaching the age atwhichsuchdiseasestypicallydevelop.In ordertoevaluatetheeffectivenessofsucha hypothesis at explaining changes in ALS incidence, Pritchard & Sunak examine the changing patterns of ALS incidence, prevalence, and mortality from both a public health/policy and

epidemiological/statisticalperspective. 2.1.PublicHealthandALS A number of phenomena over the years have raised the possibility of ALS as target of public health action. The most common reason for possible in ALS public has health the

Westernization,

lending

credence

theoriesthatindigenousdietarypracticesor environmentalfactorsmayhavecausedthe increasedincidenceofthedisease.10 Dramatic variation in ALS incidence has

involvement

been

identificationofdiseaseclustersparticular geographic locations or social relations in

EpidemiologyofALS

Page5of15

also

been

identified

in

less

exotic

ALS, then the absolute numbers of ALS deathswouldincreasewhiletherateofALS deathswouldremainconstant. TheincreaseintherateofALSmortalityin the youngerage brackets(i.e.those below the average age of ALS mortality: 60) is particularly troubling. To understand the possibleimplicationsofthistrend,Pritchard & Sunak turned to reported increases in ALS incidence among Gulf War Veterans.15 Anumberofstudiesonthephenomenonof increased rates of ALS among Gulf War Veteransrevealedthatbothmilitaryservice in general AND deployment to the Persian Gulf were associated with a higher risk of developing ALS later in life.16 Deployed troops had an ALS incidence of 57.5 per million while nondeployed troops had an incidence of 37.5 per million both above the national average of between 10 and 30 cases per million. Pritchard & Sunak interpretthesestudiesasdemonstratingthe clear involvement of multiple

geographic

locations

(including

Massachusetts, Italy, and Finland.)11 There has also been evidence of conjugal clustering of ALS (in which marriage partners are both affected by ALS an occurrence that is highly statistically improbable.)12 2.2.EpidemiologicalFindings Intheircomprehensivereview,Pritchard& Sunak interrogated the major

epidemiologicalstudiesonALSin boththe United States and elsewhere in order to developadetailedpictureofthechangesin ALS epidemiology over the past three decades.13 The key study which served as the baseline for their analysis was that of Noonan et al., who found that both the absolute numbers and the ratepermillion of ALS deaths has been increasing steadily since the late 1960s.14 Noonan and colleaguesalsofoundthatALSdeathswere increasing among women at a faster rate than among men. The evidence of the Noonan et al. study provides the first contradiction to a simple Gompertzian explanation of increased ALS incidence rates. If the increased numbers of ALS deaths were due simply to more people living to reach the typical age of onset of

environmentalfactorsintheetiologyofALS among relative young and early middle agedpatients.17 Continuingthislineofinquiry,Pritchardet al. turn to international data in order to ascertain whether the changes in ALS

EpidemiologyofALS

Page6of15

incidence (namely, increased rates of incidence across all age brackets, with the most pronounced increase among younger agebracketsandwomen)areuniquetothe United States or can be observed in other Western nations.18 In an original

mortality increased across the board, but most dramatically among women and in younger age brackets than those most frequently affected by ALS. Apart from France, the authors observed substantial increasesinbothmaleandfemaledeathsin the OND (other neurological diseases) category between 1979 and 1997. Rates of increasevariedfromcountrytocountry,but were most dramatic in Canada and the UnitedStates.22 Pritchardetal.observedsimilarpatternsof increase in Mental Disorder Death (MDD) numbers and rates. (The MDD category includes Alzheimers Disease, another neurodegenerative condition.) As with OND,U.S.ratesofMDDdeathsroseacross theboard,withthemostdramaticincreases among women and in the younger age brackets. These trends were true in a numberoftheothercountriesstudied,with the notable exception of Japan, in which bothONDandMDDneurologicaldeathsin both genders fell for all age brackets under 74overtheperiodstudied.23 In an addon to this study, Pritchard continued his analysis up to and including the year 2000 (the previous study statistics had ended in 1997), and found that the

investigation, Pritchard et al. investigated mortality from neurological diseases in a variety of countries, including Australia, Canada, England & Wales, France,

Germany, Italy, Japan, Netherlands, and Spain.19 In England & Wales, Pritchard et al.wereabletoobtainspecificdataonALS mortality, while in the other countries they relied on a broad category of neurological disease deaths due to the fact that WHO reporting does not separate out ALS as a diagnostic category.20 However, Pritchard and colleagues examined multiple sclerosis deaths in the United States and found almost identical patterns to those observed with ALS, suggesting that similar patterns of increased incidence are occurring across the range of neurological disorders which fall under the WHO category employed in theiranalysis.21 In general, Pritchard et al. found similar patterns to those observed in the United Statesinmanyofthecountriesstudied.For example, in England & Wales, ALS

EpidemiologyofALS

Page7of15

trendtowardincreasedneurologicaldeaths in Canada, England & Wales, and the U.S. continued between 1997 and 2000; in general, changes in neurological disorder deaths between 1979 and 2000 reached statistical significance in both Canada and theU.S.24 Overall,Pritchardandcolleaguesestimated that the increases in both OND and MDD death rates accounted for a total of more than 11,972 extra deaths per year (4,998 among2564yearoldsand6,974among65 74yearolds).25 Comparing deaths from all causes in the U.S. by gender, Pritchard et al. also found that the pattern of higher rates of increase among women was not unique to the neurodegenerativediseases.Ratesofdeath from mental disorders, lung cancer, circulatory disorders, infarction, and other respiratory diseases all increased among women at a greater rate than among men (all statistically significant at the p75 mg% associated with paraproteinemia3

Excitatory Amino Acids Oxidative stress/injury4

Possibility of transglutaminase levels as a marker of disease stage 8-hydroxy-2-deoxyguanosine 3-nitrotyrosine 3-nitro-4-hydroxypheol acetic acid Low molecular weight neurofilament (NF)

Cytoskeletal markers

5

Blood Oxidative stress/injury6

Increased red blood cell protein (RBC) carbonyl content as disease progresses7

Immunological markers

Increased IL-6 (associated with epidermis IL-6 staining) Auto-antibodies against fetal and juvenile CNS vasculature Increased ICE/caspase levels

Cell death / apoptosis

8

Skin General morphology9

Enhanced elastosis Edematous dermis Irregular collagen fibrils Enhanced laminin immunostaining in epithelial and blood vessel basement membrane. Enhanced type III procollagen staining of collagen bundles associated with increased urinary levels of type III procollagen Reduced type IV collagen immunostaining of basement membrane Increased cystatin in epithelial basement membrane10

Immunological markers Cell death / apoptosis11

Increased IL-6 staining of basement membrane Increased cell death following exposure to SIN-1 or H202

CurrentResearchTopicsinALS:AppendixA

Page1of3

REFERENCES

1

Reproduced from M.J. Strong, Biochemical markers: summary, ALS & Other Motor Neuron Disorders,2000,1(Suppl1):58590. F.H.Norris,etal.,Spinalfluidcellsandprotein in amyotrophic lateral sclerosis, Archives of Neurology,2001,50:48991. D.S. Younger, et al., Motor neuron disease and amyotrophic lateral sclerosis: relation of high CSF protein content to paraproteinemia and clinicalsyndromes,Neurology,1990,40:59599. A. Stevens, et al., A characteristic ganglioside antibody pattern in the CSF of patients with amyotrophic lateral sclerosis, Journal of Neurology, Neurosurgery, and Psychiatry, 1993, 56: 36164. P.J. Shaw, et al., Serum and cerebrospinal fluid markers of ALS, ALS & Other Motor Neuron Disorders,2000,1(Suppl):617.5

2

H. Tohgi, et al., Remarkable increase in cerebrospinal fluid 3nitrotyrosine in patients withsporadicamyotrophiclateralsclerosis,Ann Neurol,1998,44:6969. L.E. Rosengren, et al., Patients with amyotrophic lateral sclerosis have increased levels of neurofilament protein in CSF, J Neurochem,1996,67:20138. P.J. Shaw, et al., Serum and cerebrospinal fluid markers of ALS, ALS & Other Motor Neuron Disorders,2000,1(Suppl):617. J.A.Molina,etal.,Serumlevelsofbetacarotene, alphacarotene, and vitamin A in patients with amyotrophic lateral sclerosis, Acta Neurologica Scandinavia,1999,99:3157. P.I. Oteiza, et al., Evaluation of antioxidants, protein, and lipid oxidation products in blood from sporadic amyotrophic lateral sclerosis patients,NeurochemRes,1997,22:5359.7

6

3

W.Camu,etal.,FastingplasmaandCSFamino acid levels in amyotrophic lateral sclerosis: a subtypeanalysis,ActaNeurolScand,1993,88:51 55. H. Tumani, Glutamine synthetase in cerebrospinalfluid,serum,andbrain,Archivesof Neurology,1999,56:12416. K. Fujita, et al., Transglutaminase activity in serum and cerebrospinal fluid in sporadic amyotrophiclateralsclerosis:apossibleuseasan indicator of extent of the motor neuron loss, JournaloftheNeurologicalSciences,1998,158:537.

S.Ono,etal.,Increasedinterleukin6ofskinand serum in amyotrophic lateral sclerosis, J Neurol Sci,2001,187:2734. I. NiebrojDobosz, Antineuronal antibodies in serum and cerebrospinal fluid of amyotrophic lateral sclerosis patients, Acta Neurologica Scandinavia,1999,100:23843. A. Pestronk, Serum antibodies to GM1 ganglioside in amyotrophic lateral sclerosis, Neurology,1988,38:145761.

8

4

M. Anagnostouli, et al., Cerebrospinal fluid levels of biotin in various neurological disorders,ActaNeurologicaScandinavia,1999,99: 38792. M.B. Bogdanov, et al., Increased oxidative damage to DNA in ALS patients, Free Rad Biol Med,2000,29:652658. F.M. Beal, Increased 3nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis,AnnNeurol,1997,42:64654. H. Tohgi, et al., Increase in oxidized NO products and reduction in oxidized glutathione in cerebrospinal fluid from patients with sporadic form of amyotrophic lateral sclerosis, NeurosciLett,1999,260:2046.9

J. Hzecka, et al., Interleukin1b converting enzyme/caspase I (ICE/caspase1) and soluble APO1/Fas/CD95receptorinamyotrophiclateral sclerosis patients, Acta Neurologica Scandinavia, 2001,103:2558. H.M. Fullmer, et al., A cutaneous disorder of connectivetissueinamyotrophiclateralsclerosis: ahistochemicalstudy,Neurology,1960,717724. G. Kolde, et al., Skin involvement in amyotrophic lateral sclerosis, Lancet, 1996, 347: 1227. S. Ono, et al., Increased expression of insulin likegrowthfactorIinskininamyotrophiclateral sclerosis,EurJNeurol,2000,69:199203.

EpidemiologyofALS:AppendixA

Page2of 3

S.Ono,Decreasedurinaryconcentrationoftype IVcollageninamyotrophiclateralsclerosis,Acta NeurologicaScandinavia,1999,100:37784. S.Ono,etal., Decreasedurinaryconcentrations of type IV collagen in amyotrophic lateral sclerosis, Acta Neurologica Scandinavia, 1999, 100:1116. S. Ono, et al., Increased cystatin C immunoreactivity in the skin in amyotrophic lateral sclerosis, Acta Neurologica Scandinavia, 2000,102:4752.10

S.Ono,etal.,Increasedinterleukin6ofskinand serum in amyotrophic lateral sclerosis, J Neurol Sci,2001,187:2734. G.A. Jansen, et al., Evidence against increased oxidative stress in fibroblasts from patients with nonsuperoxidedismutase1 mutant familial ALS,JNeurolSci,1999,139:9194. T. Aguirre, et al., Increased sensitivity of fibroblasts from amyotrophic lateral sclerosis patientstooxidativestress,AnnNeurol,1998,43: 4527.

11

EpidemiologyofALS:AppendixA

Page3of 3

AppendixB:InVitroModelsofALSCitedinarticlespublishedbetweenJan2005andJun2005

Source Mouse Mouse Mouse Rat/Mouse

Types of Cells NSC34 (hybrid of motor neurons and neuroblastoma cells) N2a (neuroblastoma cells) Spinal motor neurons ND7 (hybrid of post-mitotic rat neonatal dorsal root ganglion neurons and mouse neuroblastoma cells) VSC 4.1 (rat motor neuroblastoma cells) neurons/mouse

Disease-causing agent mSOD-1 expression1 mSOD-1 expression2 mSOD-1 expression3 mSOD-1 expression4

Rat/mouse Rat Rat Human Human Rat Rat Rat Rat

mSOD-1 expression5

Embryonic ventral spinal cord cells seeded onto neonatal Schwann cells6 Motor neurons & astrocytes Fetal cerebral cells Fetal cerebral cells Astrocytes Spinal cord astrocytes Lumbar spinal cord cultures Lumbar spinal cord cultures AMPA toxicity (to motor neurons only)7 TNF-alpha toxicity8 Tat and gp120 (HIV proteins) toxicity9 Glyoxal (glutamate inhibitor) toxicity10 FGF-1 toxicity11 THA (threohydroxyaspartate, a glutamate uptake blocker) toxicity12 PDC (L-trans-pyrrolidine-2,4dicarboxylate, a glutamate uptake blocker) toxicity13 Chronic echovirus 6 infection14 Increased expression of EAAT2 via recombinant virus infection15 transporter-1

Human Mouse

Glial cell precursors Hippocampal slice cultures

CurrentResearchTopicsinALS:AppendixB

Page1of2

REFERENCES

1

Kirby J, et al., Mutant SOD1 alters the motor neuronal transcriptome: implications forfamilialALS,Brain.2005May4;[Epub ahead of print]; M. Rizzardini, et al., Low levels of ALSlinked Cu/Zn superoxide dismutase increase the production of reactive oxygen species and cause mitochondrial damage and death in motor neuronlike cells, J Neurol Sci, 2005, 232(1):95103. Takamiya R, et al., Overexpression of mutated Cu,ZnSOD in neuroblastoma cells resultsincytoskeletalchange.AmJPhysiol Cell Physiol. 2005 Feb;288(2):C2539. Epub 2004Sep29. Kuo JJ, at al., Increased persistent Na(+) current and its effect on excitability in motoneurones cultured from mutant SOD1 mice,JPhysiol.2005Mar15;563(Pt3):843 54.Epub2005Jan13. Y.J. Patel, et al., Hsp27 and Hsp70 administered in combination have a potent protective effect against FALSassociated SOD1mutantinduced cell death in mammalian neuronal cells, Brain Res Mol BrainRes,2005,134(2):25674. H.J. Kim, et al., Pyruvate protects motor neurons expressing mutant superoxide dismutase 1 against copper toxicity, Neuroreport,2005,16(6):5859. Haastert K, Grosskreutz J, Jaeckel M, LadererC,BuflerJ,GrotheC,ClausP.Rat embryonic motoneurons in longterm co culture with Schwann cellsa system to investigate motoneuron diseases on a cellular level in vitro. J Neurosci Methods. 2005Mar30;142(2):27584. Platania P, et al., 17betaestradiol rescues spinal motoneurons from AMPAinduced toxicity:Aroleforglialcells,NeurobiolDis, 2005May10;[Epubaheadofprint]

8

M.A. Williams, et al., Protection of human cerebral neurons from neurodegenerative insults by gene delivery of soluble tumor necrosisfactorp75receptor,ExpBrainRes, 2005,epub. Ibid. M. Kawaguchi, et al., Glyoxal inactivates glutamate transporter1 in cultured rat astrocytes, Neuropathology, March 2005, 25(1):2736. P. Cassina, et al., Astrocyte activation by fibroblastgrowthfactor1andmotorneuron apoptosis: implications for amyotrophic lateralsclerosis,JNeurochem,2005,93(1):38 46; M.R. Vargas, et al., Fibroblast growth factor1 induces heme oxygenase1 via nuclear factor erythroid 2related factor 2 (Nrf2) in spinal cord astrocytes: consequences for motor neuron survival, J BiolChem,2005,epub. E.Matyja,etal.,Themodeofspinalmotor neurons degeneration in a model of slow glutamate excitotoxicity in vitro, Folio Neuropathol,2005,43(1):713. Ibid. F. Beaulieux, et al., Cumulative mutations in the genome of Echovirus 6 during establishment of a chronic infection in precursors of glial cells, Virus Genes, 2005, 30(1):10312. J.V. Selkirk, et al., Overexpression of the humanEAAT2glutamatetransporterwithin neuronsofmouseorganotypichippocampal slice cultures leads to increased vulnerabilityofCA1pyramidalcells,EurJ Neurosci,2005,21(8):22916.

9

10

2

11

3

4

12

13 14

5

6

15

7

CurrentResearchTopicsinALS:AppendixB

Page2of2

SelectedAdditionalResourcesonALS

SectionI.OrganizationalResources: MajorALSClinicsandResearchCenters ALSResearchandPatientCareCenter,UniversityofCalifornia,SanFrancisco 350ParnassusAvenue,Suite500 SanFrancisco,California94117 Phone:4154767581 MedicalDirector:CatherineLomenHoerth,M.D.,PhD. ForbesNorrisMDA/ALSResearchCenter,CaliforniaPacificMedicalCenter 2324SacramentoStreet,#150 SanFrancisco,CA94115 Phone:4159233604 MedicalDirector:RobertG.Miller,M.D. UCLAALSClinicandResearchUnit 300MedicalPlaza LosAngeles,CA900956975 Phone:3108252937 MedicalDirector:MichaelC.Graves,M.D. YaleUniversityMDA/ALSClinic YaleUniversitySchoolofMedicine Neurology,LCI702333CedarSt. NewHaven,CT06510 Phone:2037854085 MedicalDirector:JonathanM.Goldstein,M.D. KessenichFamilyMDAALSCenter UniversityofMiamiSchoolofMedicine 1150NW14StSuite700 Miami,Fl33136 Phone:1800690ALS1(6902571) Website:http://www.miamials.org MedicalDirector:WalterBradley,D.M.,F.R.C.P. TheLoisInsoliaALSCenter NorthwesternUniversityMedicalSchool DepartmentofNeurology,Tarry13715 NorthwesternUniversityMedicalSchool 303EastChicagoAvenue

Chicago,Illinois60611 Phone:3125034737 ProgramDirector:TeepuSiddiqueM.D. TheUniversityofChicagoMDA/ALSClinic TheUniversityofChicago 5841S.Maryland Chicago,Illinois606371463 Phone:7737025546or7737026221 Website:http://ucneurology.uchicago.edu Directors:RaymondP.RoosM.D.,BettySolivenM.D. IndianaUniversityMedicalCenterALSProgram DepartmentofNeurologyRG6 IndianaUniversitySchoolofMedicine 1050WestWalnutStreet Indianapolis,Indiana46202 Phone:3176307004 Medicaldirector:RobertM.Pascuzzi,M.D. UniversityofKentuckyandVeteransAffairsMedicalCentersALSClinic DepartmentofVeteransAffairsMedicalCenter 1101VeteransDrive Lexington,Kentucky405022236 Phone:6062814920 Website:http://www.mc.uky.edu/neurology/neur.htm Medicaldirector:EdwardJ.Kasarskis,M.D.,Ph.D. JohnHopkinsUniversitySchoolofMedicineMDA/ALSNeuromuscularClinic 600N.WolfeSt. Baltimore,MD21287 Phone:4106143846 Website:http://www.alscenter.org MedicalCodirectors:JeffreyD.RothsteinM.D.,Ph.D.,DanialB.Drachman,M.D. MassachusettsGeneralHospitalNeuromuscularClinic MassachusettsGeneralHospital WangACC,Room835 Boston,Massachusetts021142792 Phone:6177243914 DirectorofNeuromuscularClinic:RobertH.Brown,Jr.,D.Phil.,M.D. MedicalCoDirectorofALSClinicandDirectorofClinicalTrialsUnit:MeritE.Cudkowciz,M.D. MotorNeuronDiseaseClinic UniversityofMichiganMedicalCenter 1324/0322TaubmanCenter 1500EastMedicalCenterDrive

AnnArbor,MI481090316 Phone:3139369010 Director:JohnJ.Wald,M.D. Neuromuscular&ALSCenter RobertWoodJohnsonUniversityHospitalandUMDNJ 97PatersonStreet NewBrunswick,NJ089010019 Phone:7322357331 Website:http://www2.umdnj.edu/nmalsweb MedicalDirector:JerryM.Belsh,M.D. EleanorandLouGehrigMDA/ALSCenter NeurologicalInstitute,ColumbiaUniversityMedicalCenter 710West168thStreet,Box107 NewYork,NewYork10032 Phone:2123051319 Website:http://www.columbiaALS.org/ MedicalDirector:HiroshiMitsumoto,M.D. TheMDA/ALSProgramatMountSinaiMedicalCenter 5East98Street,7thfloor NewYork,NewYork10029 Phone:2122418674 Website:http://www.mssm.edu/neurology/neuromuscular/als MedicalDirector:DaleJ.Lange,M.D. BethIsraelALSCenter 10UnionSquareEast,Suite2Q NewYork,NewYork10003 Phone:2127203050 MedicalDirector:StephenScelsa,MD ALSResearchandTreatmentCenter StateUniversityofNewYorkHealthScienceCenter 750EastAdamsStreet Syracuse,NewYork13210 Phone:3154645358 MedicalDirector:JeremyM.Shefner,M.D.,PhD TheALSCenterofWakeForestUniversityBaptistMedicalCenter MedicalCenterBoulevard WinstonSalem,NorthCarolina271571078 Phone:3367164101 Website:http://www.wfubmc.edu/neurology/ MedicalDirector:PeterD.Donofrio,M.D

CarolinasNeuromuscular/ALSCenter CarolinasMedicalCenter POBox32861 Charlotte,NorthCarolina282322861 Phone:7044466ALS(6257)or18009247620 Medicaldirector:JeffreyRosenfeld,M.D.,Ph.D. DukeUniversityMedicalCenterMDA/ALSClinic Box3333DukeUniversityMedicalCenter 932MorreeneRoad Durham,NorthCarolina27710 Phone:9196682839 MedicalDirector:RichardS.BedlackM.D.,PhD CenterforALSandRelatedDisorders ClevelandClinicFoundation 9500EuclidAvenue Cleveland,Ohio44195 Phone:2164448638 MedicalDirector:ErikP.Pioro,M.D.,PhD ALSAssociationCenteratthePennNeurologicInstitute TheUniversityofPennsylvaniaandPennsylvaniaHospital 330South9thStreet Philadelphia,Pennsylvania19107 Phone:2158296500 Website:http://neurology.med.upenn.edu/~als/ Medicaldirector:LeoMcCluskey,M.D. MDA/ALSCenterofDallasClinic UniversityofTexasSouthwesternMedicalCenter DepartmentofNeurology 5161HarryHinesBlvd. Dallas,Texas75235 Phone:2146486419 Codirectors:WilsonW.Bryan,M.D.,JeffreyL.Elliott,M.D. BaylorCollegeofMedicineMDA/ALSCenter DepartmentofNeurology 6501FanninStreetNB302 Houston,Texas77030 Phone:7137984073 MedicalDirector:StanleyH.Appel,M.D.

ALS/MSClinicalResearchCenter UniversityofWisconsinHospitalandClinics 600HighlandAvenue,RoomH6/563CSC Madison,WI537925132 Phone:6082639057 MedicalDirector:BenjaminRixBrooks,M.D. Nonprofit(NonAcademic)ResearchCenters ALSTherapyDevelopmentFoundation 215FirstStreet Cambridge,MA02142 Phone:6174417200 Website:http://www.als.net

SectionII.PatientInformationResources InformationforNewlyDiagnosedPatients WhatisALS? ALSTherapyDevelopmentFoundation URL:http://www.als.net/als101/whatisals.asp TipsforNewlyDiagnosedALSPatients WillHubben/ALSAssociation URL:http://alsa.org/community/article.cfm?id=383& ALSAGuideforPatients Dr.EricLivingston URL:http://home.earthlink.net/~jakesan/pages/guide1.html ALSABeginnersManual CecilNeth URL:http://www.alscecilneth.net/ WhatisALS?ForKids ALSMarchofFaces URL:http://www.marchoffaces.org/KIDS/moe1.html

Local(Massachusetts)SupportGroups MDAsponsoredSupportGroups Cantonareasupportgroups:7815751881 Bostonareasupportgroups:6173482155 AtholSupportGroup AtholMemorialHospital 2033MainSt.,Athol,MA MeetsthelastThursdayofeachmonthfrom6:30p.m.8:00p.m. DedhamSupportGroup TraditionsAssistedLiving 735WashingtonStreet,Dedham,MA. Meetsonthe4thWednesdayofeverymonthfrom7:30p.m.9:00p.m. MethuenSupportGroup HolyFamilyHospital 70EastStreet,Methuen,MA MeetsonthelastWednesdayofeverymonthfrom6:30p.m.8:30p.m. NorthDartmouthSupportGroup TheCedars 628OldWestportRoad,Dartmouth,MA (508)3660690 Meetsonthe4thThursdayofeverymonthfrom6:00p.m.to8:00p.m.(doesnotmeetJulyor August.) PeabodySupportGroup LaheyClinicNorthshore OneEssexCenterDrive,Peabody,MA 9785384300 Meetsonthe4thThursdayofeverymonthfrom7:00p.m.8:30p.m. Online/EmailSupportGroups ALSDigest Emailbasedforumandsupportgroup. Howtojoin:[email protected]. ALSChatRooms AlistofandinstructionsonparticipatinginMDAsponsoredonlinechatroomsontopicsrelating toALS. Howtojoin:Visithttp://als.mdausa.org/chat/index.cfm

LivingwithALS OnlinesupportgroupforpeoplewithALSandtheircaregivers.Thegroupisprimarilydirected towardsharinginformationandideasonusingpalliativeandassistivetechnologiestoeasethe burdenoflivingwithALS. Howtojoin:Visithttp://health.groups.yahoo.com/group/livingwithals/ BraintalkForums:ALS OnlinesupportgroupandforumforpeoplewithALSandtheircaregivers.TheBraintalkforum ishighlyfocusedonemergingtherapies,alternativemedicine,newresearch,andothertopics relatedtothetreatmentandpossiblecureofALS. Howtojoin: http://neuromancer.mgh.harvard.edu/cgi bin/forumdisplay.cgi?action=topics&forum=ALS&number=3 InformationonClinicalTrialsinALS ClinicalTrials&StudiesofNeuromuscularDisease MDAUSA(ALSDivision) URL:http://www.mdausa.org/research/ctrials.cfm DrugDevelopmentUpdate ALSAssociation URL:http://www.alsa.org/patient/drug.cfm?CFID=906529&CFTOKEN=47942698 CurrentClinicalTrials ALSTherapyDevelopmentFoundation URL:http://www.als.net/research/studies/currentClinicalTrialList.asp

SectionIII.MajorFundraisingandAdvocacyOrganizations ALSAssociation www.alsa.org TheALSAssociationisanationalnotforprofithealthagencyprovidingpatientandcommunity services,publiceducation,patientadvocacyandresearch.TheAssociationsaffiliatenetwork includeschaptersincommunitiesthroughoutthenation. ALSMarchofFaces www.marchoffaces.org PromotesALSawarenessandadvocacyandisoperatedbyALSpatientsandcaregivers.

HopeforALS http://www.hopeforals.org HopeforALSisaHoustonbasednonprofitwithamissiontoraiseresearchfundsnecessaryto findeffectivetreatmentsforthosesufferingfromALStoday. HopeHappens(formerly:ALSHope) www.alshope.org HopeHappensaidsthesearchforacureforALSbyfundingprogressiveresearchandhopesin theprocesstocreateanewmethodologyforfunding,researching,anddevelopingtreatmentsfor otherneurologicaldisorders. LesTurnerALSFoundation www.lesturnerals.org TheLesTurnerALSFoundationisdevotedtothetreatmentandeliminationofamyotrophic lateralsclerosis(ALS),betterknownasLouGehrigsdisease,andisbasedinChicago. MuscularDystrophyAssociation,ALSDivision http://als.mdausa.org Sincetheearly1950s,whenEleanorGehrigservedasanationalvolunteerleaderofMDA,the AssociationhasassistedthoseaffectedbyALS.MDAsALSDivisionoffersacomprehensive rangeofservicesforpatientsandcaregivers,andaidsthesearchforatreatmentorcurethrough anaggressive,internationalresearchprogram. ProjectA.L.S. www.projectals.org ProjectA.L.S.isanotforprofitorganizationdedicatedtofindingacureforALS,findingan effectivetreatmentforpeoplelivingwithA.L.S.,andraisingawarenessaboutA.L.S.Current researchprojectsfocusongenechiptechnology,accelerateddrugtesting,andneuralstemcell replacement. RideforLife www.rideforlife.org HoldsanannualfundraisingeventinwhichALSpatientsridetheirelectricwheelchairsdown thehighwaysandbywaystoraisefundsforacureandraiseawareness.Duringthepast7years, theridehasraisedmorethan1milliondollars.