Amyotrophic Lateral Sclerosis and the Innate Immune System

NCT02869048 | Recruiting DMC

• 1 other identifier: H-16017145
• Study Type: observational
• Target: 375
• Locations: 1 country
• Sites: 8

Brief Summary

Amyotrophic Lateral Sclerosis (ALS) is an aggressive, deadly disease. ALS leads to destruction of the neural pathways which control the conscious movements of the muscles. This destruction leads to muscular dystrophy with increasing difficulties in moving, breathing, swallowing, and speaking. In the last phase of an ALS patient's life it is necessary with respiratory therapy in order to breathe. In average an ALS patient lives 3 years from the time he or she gets the diagnose. The cause of the disease is still unknown and there is currently no treatment which can stop the progression of the disease. Former clinical studies have indicated that the innate immune system and in particular the complement system plays a significant role in the progression of ALS. The complement system, which is activated in cascades, is part of the innate system but participates in the innate as well as the acquired immune system. Former clinical trials have been characterized by limited knowledge about both the complement system as well as to how it is measured. Today it is possible to measure directly on the different components of the complement system and to understand its contribution to the overall immune response. It is also possible today to detect defects of the complement system. All these progressions are the foundation for this project which is carried out in close cooperation with one of the world's leading researchers in the complement system, professor Peter Garred from Rigshospitalet. The aim is to make a national research project about ALS in order to investigate the role of the innate immune system, and especially the complement system, in patients with ALS. In the long term the hope is, that this will lead the way to a targeted and effective medical treatment to the people affected by this grave disease.

Conditions

Amyotrophic Lateral Sclerosis; Neurodegenerative Disease; Motor Neuron Disease

Keywords

Biological Specimen Banks; Innate Immunity; Clinical Study; Complement system proteins; Amyotrophic lateral sclerosis; Neurodegenerative disease; Motor neuron disease

Outcome Measures

Primary Outcomes (1)

• Complement activity

  The complement activity (measured by haemolytic capacity, complement-activation potential and specific mediators) in ALS patients and compared with 2 control groups.

  0-10 year

Secondary Outcomes (8)

• Subcomponents of the complement cascade

  0-10 years

• Inactivation of the complement system

  0-2 years

• Indirect profiling of inflammatory proteins present in the blood

  0-10 years

• Cytokines present in the blood

  0-10 years

• Acut phase reactants

  0-10 years

Study Arms (3)

ALS patients

Patients diagnosed with ALS will be included in this group. Blood and spinal fluid samples will be stored in biobank and later analyzed. A subset of this group (20 ALS patients) will give blood and spinal fluid every 6 months during progression of the disease. A subset of 10 will donate a muscle biopsy.

Control group with patients with other neurological disease

Patients referred to hospital with symptoms of acute or chronic headache.

Neurologically healthy control group

Patients having orthopaedic surgery performed in spinal anaesthesia.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

ALS group: Patients diagnosed with certain or likely ALS Neurological control group: Patients being examined for cronical headache or being referred to hospital to get a lumbar perfusion test performed. Neurologically healthy control group: Clinical study 1: Healty employees from Rigshospitalet Clinical study 2: Neurologically healthy patients having planned orthopaedic surgery performed in spinal anaestesia.

You may qualify if:

• For ALS group:Diagnosed with the diagnose category "certain ALS" or "likely ALS according to the El Escorial rev. diagnose criteria
• For Neurological control group: Referred to neurological department to be examined for acute or chronic headache or referred to get a lumbar perfusion test performed.

You may not qualify if:

• For all groups (Clinical study 2-3): permanent contraindication for having a lumbar puncture performed
• For Neurological control group: Known with chronic inflammatory disease or autoimmune disease.
• For healthy control group (clinical study 1): Known with any disease
• For healthy control group (clinical study 1): Taking daily medication
• For Neurologically healthy control group (Clinical study 2): Known with neurological disease
• For Neurologically healthy control group (Clinical study 2): Known with chronic inflammatory disease or autoimmune disease.

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead
• Zealand University Hospital: collaborator
• Bispebjerg Hospital: collaborator
• Aarhus University Hospital: collaborator
• Odense University Hospital: collaborator

Study Sites (8)

Dept. of Neurology Aarhus Hospital, Nørrebrogade

Aarhus, 8000, Denmark

RECRUITING

Gildhøj Private Hospital

Brøndby, 2605, Denmark

COMPLETED

Clinic of neuroanestesiology, Rigshospitalet Glostrup

Copenhagen, 2600, Denmark

RECRUITING

Dept. of Neurology, Bisbebjerg Hospital

Copenhagen NV, 2400, Denmark

RECRUITING

Clinic of Neurosurgery, Rigshospitalet

Copenhagen Ø, 2100, Denmark

NOT YET RECRUITING

The Dept. og Neurology, Rigshospitalet Glostrup

Glostrup Municipality, 2600, Denmark

RECRUITING

Dept. of Neurology, Odense Hospital

Odense C, 5000, Denmark

RECRUITING

The dept. of Neurology, Roskilde Hospital

Roskilde, 4000, Denmark

RECRUITING

Related Publications (37)

• Andersen PM, Al-Chalabi A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol. 2011 Oct 11;7(11):603-15. doi: 10.1038/nrneurol.2011.150.

  PMID: 21989245 BACKGROUND

• Tumer Z, Bertelsen B, Gredal O, Magyari M, Nielsen KC, Lucamp, Gronskov K, Brondum-Nielsen K. Novel heterozygous nonsense mutation of the OPTN gene segregating in a Danish family with ALS. Neurobiol Aging. 2012 Jan;33(1):208.e1-5. doi: 10.1016/j.neurobiolaging.2011.07.001. Epub 2011 Aug 26.

  PMID: 21852022 BACKGROUND

• Phukan J, Pender NP, Hardiman O. Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurol. 2007 Nov;6(11):994-1003. doi: 10.1016/S1474-4422(07)70265-X.

  PMID: 17945153 BACKGROUND

• Brooks BR, Miller RG, Swash M, Munsat TL; World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Dec;1(5):293-9. doi: 10.1080/146608200300079536. No abstract available.

  PMID: 11464847 BACKGROUND

• Seals RM, Hansen J, Gredal O, Weisskopf MG. Age-period-cohort analysis of trends in amyotrophic lateral sclerosis in Denmark, 1970-2009. Am J Epidemiol. 2013 Oct 15;178(8):1265-71. doi: 10.1093/aje/kwt116. Epub 2013 Sep 24.

  PMID: 24064744 BACKGROUND

• Chio A, Logroscino G, Traynor BJ, Collins J, Simeone JC, Goldstein LA, White LA. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology. 2013;41(2):118-30. doi: 10.1159/000351153. Epub 2013 Jul 11.

  PMID: 23860588 BACKGROUND

• Annunziata P, Volpi N. High levels of C3c in the cerebrospinal fluid from amyotrophic lateral sclerosis patients. Acta Neurol Scand. 1985 Jul;72(1):61-4. doi: 10.1111/j.1600-0404.1985.tb01548.x.

  PMID: 4050318 BACKGROUND

• Apostolski S, Nikolic J, Bugarski-Prokopljevic C, Miletic V, Pavlovic S, Filipovic S. Serum and CSF immunological findings in ALS. Acta Neurol Scand. 1991 Feb;83(2):96-8. doi: 10.1111/j.1600-0404.1991.tb04656.x.

  PMID: 2017904 BACKGROUND

• Conradi S, Ronnevi LO. Cytotoxic activity in the plasma of amyotrophic lateral sclerosis (ALS) patients against normal erythrocytes. Quantitative determinations. J Neurol Sci. 1985 May;68(2-3):135-45. doi: 10.1016/0022-510x(85)90095-4.

  PMID: 4009202 BACKGROUND

• Conradi S, Ronnevi LO. Immunoglobulin-mediated cytotoxic effect of ALS-plasma towards erythrocytes: reflexion of a pathogenetic mechanism? Adv Exp Med Biol. 1987;209:7-13. doi: 10.1007/978-1-4684-5302-7_2. No abstract available.

  PMID: 3577932 BACKGROUND

• Digby J, Harrison R, Jehanli A, Lunt GG, Clifford-Rose F. Cultured rat spinal cord neurons: interaction with motor neuron disease immunoglobulins. Muscle Nerve. 1985 Sep;8(7):595-605. doi: 10.1002/mus.880080709.

  PMID: 4047091 BACKGROUND

• Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A, Khan J, Polak MA, Glass JD. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol. 2004 Feb;185(2):232-40. doi: 10.1016/j.expneurol.2003.10.004.

  PMID: 14736504 BACKGROUND

• Frey D, Schneider C, Xu L, Borg J, Spooren W, Caroni P. Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases. J Neurosci. 2000 Apr 1;20(7):2534-42. doi: 10.1523/JNEUROSCI.20-07-02534.2000.

  PMID: 10729333 BACKGROUND

• Goldknopf IL, Sheta EA, Bryson J, Folsom B, Wilson C, Duty J, Yen AA, Appel SH. Complement C3c and related protein biomarkers in amyotrophic lateral sclerosis and Parkinson's disease. Biochem Biophys Res Commun. 2006 Apr 21;342(4):1034-9. doi: 10.1016/j.bbrc.2006.02.051. Epub 2006 Feb 20.

  PMID: 16516157 BACKGROUND

• Grewal RP, Morgan TE, Finch CE. C1qB and clusterin mRNA increase in association with neurodegeneration in sporadic amyotrophic lateral sclerosis. Neurosci Lett. 1999 Aug 13;271(1):65-7. doi: 10.1016/s0304-3940(99)00496-6.

  PMID: 10471215 BACKGROUND

• Heurich B, El Idrissi NB, Donev RM, Petri S, Claus P, Neal J, Morgan BP, Ramaglia V. Complement upregulation and activation on motor neurons and neuromuscular junction in the SOD1 G93A mouse model of familial amyotrophic lateral sclerosis. J Neuroimmunol. 2011 Jun;235(1-2):104-9. doi: 10.1016/j.jneuroim.2011.03.011. Epub 2011 Apr 17.

  PMID: 21501881 BACKGROUND

• Kawamata T, Akiyama H, Yamada T, McGeer PL. Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Pathol. 1992 Mar;140(3):691-707.

  PMID: 1347673 BACKGROUND

• Kong J, Xu Z. Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J Neurosci. 1998 May 1;18(9):3241-50. doi: 10.1523/JNEUROSCI.18-09-03241.1998.

  PMID: 9547233 BACKGROUND

• Lee JD, Kamaruzaman NA, Fung JN, Taylor SM, Turner BJ, Atkin JD, Woodruff TM, Noakes PG. Dysregulation of the complement cascade in the hSOD1G93A transgenic mouse model of amyotrophic lateral sclerosis. J Neuroinflammation. 2013 Sep 26;10:119. doi: 10.1186/1742-2094-10-119.

  PMID: 24067070 BACKGROUND

• Liveson J, Frey H, Bornstein MB. The effect of serum from ALS patients on organotypic nerve and muscle tissue cultures. Acta Neuropathol. 1975 Aug 11;32(2):127-31. doi: 10.1007/BF00689566.

  PMID: 1166766 BACKGROUND

• Lobsiger CS, Boillee S, Cleveland DW. Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7319-26. doi: 10.1073/pnas.0702230104. Epub 2007 Apr 26.

  PMID: 17463094 BACKGROUND

• Lobsiger CS, Boillee S, Pozniak C, Khan AM, McAlonis-Downes M, Lewcock JW, Cleveland DW. C1q induction and global complement pathway activation do not contribute to ALS toxicity in mutant SOD1 mice. Proc Natl Acad Sci U S A. 2013 Nov 12;110(46):E4385-92. doi: 10.1073/pnas.1318309110. Epub 2013 Oct 29.

  PMID: 24170856 BACKGROUND

• Overgaard K, Werdelin L, Sorensen H, Mogensen P, Boysen G. Cytotoxic activity in plasma from patients with amyotrophic lateral sclerosis. Neurology. 1991 Jun;41(6):925-7. doi: 10.1212/wnl.41.6.925.

  PMID: 2046943 BACKGROUND

• Pinter MJ, Waldeck RF, Wallace N, Cork LC. Motor unit behavior in canine motor neuron disease. J Neurosci. 1995 May;15(5 Pt 1):3447-57. doi: 10.1523/JNEUROSCI.15-05-03447.1995.

  PMID: 7751923 BACKGROUND

• Roisen FJ, Bartfeld H, Donnenfeld H, Baxter J. Neuron specific in vitro cytotoxicity of sera from patients with amyotrophic lateral sclerosis. Muscle Nerve. 1982 Jan;5(1):48-53. doi: 10.1002/mus.880050109.

  PMID: 7057805 BACKGROUND

• Conradi, S. Cytotoxic factor in plasma from ALS patients provokes haemolysis of normal erythrocytes. Acta Neurologica Scandinavica, 65: 246-247, 1982

  BACKGROUND

• Ronnevi LO, Conradi S. Increased fragility of erythrocytes from amyotrophic lateral sclerosis (ALS) patients provoked by mechanical stress. Acta Neurol Scand. 1984 Jan;69(1):20-6. doi: 10.1111/j.1600-0404.1984.tb07775.x.

  PMID: 6702416 BACKGROUND

• Ronnevi LO, Conradi S, Karlsson E, Sindhupak R. Nature and properties of cytotoxic plasma activity in amyotrophic lateral sclerosis. Muscle Nerve. 1987 Oct;10(8):734-43. doi: 10.1002/mus.880100810.

  PMID: 3683447 BACKGROUND

• Sta M, Sylva-Steenland RM, Casula M, de Jong JM, Troost D, Aronica E, Baas F. Innate and adaptive immunity in amyotrophic lateral sclerosis: evidence of complement activation. Neurobiol Dis. 2011 Jun;42(3):211-20. doi: 10.1016/j.nbd.2011.01.002. Epub 2011 Jan 8.

  PMID: 21220013 BACKGROUND

• Tsuboi Y, Yamada T. Increased concentration of C4d complement protein in CSF in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 1994 Jul;57(7):859-61. doi: 10.1136/jnnp.57.7.859.

  PMID: 8021681 BACKGROUND

• Wolfgram F, Myers L. Amyotrophic lateral sclerosis: effect of serum on anterior horn cells in tissue culture. Science. 1973 Feb 9;179(4073):579-80. doi: 10.1126/science.179.4073.579.

  PMID: 4119685 BACKGROUND

• Woodruff TM, Costantini KJ, Crane JW, Atkin JD, Monk PN, Taylor SM, Noakes PG. The complement factor C5a contributes to pathology in a rat model of amyotrophic lateral sclerosis. J Immunol. 2008 Dec 15;181(12):8727-34. doi: 10.4049/jimmunol.181.12.8727.

  PMID: 19050293 BACKGROUND

• Pun S, Santos AF, Saxena S, Xu L, Caroni P. Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci. 2006 Mar;9(3):408-19. doi: 10.1038/nn1653. Epub 2006 Feb 12.

  PMID: 16474388 BACKGROUND

• Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012 Mar 14;2012(3):CD001447. doi: 10.1002/14651858.CD001447.pub3.

  PMID: 22419278 BACKGROUND

• Pittock SJ, Lennon VA, McKeon A, Mandrekar J, Weinshenker BG, Lucchinetti CF, O'Toole O, Wingerchuk DM. Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol. 2013 Jun;12(6):554-62. doi: 10.1016/S1474-4422(13)70076-0. Epub 2013 Apr 26.

  PMID: 23623397 BACKGROUND

• Armitage P BG. Statistical Methods for Medical Researchers. Blackwell1994.

  BACKGROUND

• Kjaeldgaard AL, Pilely K, Olsen KS, Lauritsen AO, Pedersen SW, Moller K, Garred P. Amyotrophic lateral sclerosis and the innate immune system: protocol for establishing a biobank and statistical analysis plan. BMJ Open. 2020 Aug 5;10(8):e037753. doi: 10.1136/bmjopen-2020-037753.

  PMID: 32759248 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Serum, EDTA-plasma, Hirudin-plasma, Heparin-plasma and RNAlater samples (with fullblood) will be kept in biobank as well as analyzed according design and methods of Clinical study 1+2+3. Spinal liquid sample will also be kept in biobank (Clinical Study 2+3). 10 muscle biopsies from ALS patients will be analyzed (Clinical study 4)

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Motor Neuron Disease

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Kirsten Møller, Prof., MD

  Clinic of Neuroanestesiology, Rigshospitalet, Denmark

  STUDY CHAIR

• Peter Garred, Prof., MD

  Department of Clinical Immunology

  STUDY CHAIR

• Stephen Wørlich Pedersen, dr.med

  Dept. of Neurology, Rigshospitalet Glostrup

  STUDY CHAIR

• Karsten Skovgaard Olsen, Dr.med.

  Clinic of Neuroanaestesiology, Rigshospitalet Glostrup

  STUDY CHAIR

• Anne Øberg Lauritsen, MD

  Clinic of Neuroanaestesiology, Rigshospitalet Glostrup

  STUDY CHAIR

• Eva Løbner Lund, MD, PhD

  Dept. of Pathology, Rigshospitalet

  STUDY CHAIR

• Anne-Lene Kjældgaard, MD

  Clinic of Neuroanaestesiology, Rigshospitalet Glostrup

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Anne-Lene Kjældgaard, MD

CONTACT

akja004@regionh.dk

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Ph.d.-student, MD

Study Record Dates

• First Submitted: June 28, 2016
• First Posted: August 16, 2016
• Study Start: June 1, 2016
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026
• Last Updated: October 6, 2017

Record last verified: 2017-10

Data Sharing

• IPD Sharing: Will not share

Locations

DK (8)