Initial presentation of ALS varies between affected individuals, and typically presents as spinal-onset disease (muscle weakness of the limbs), or bulbaronset disease (difficulty with speech and swallowing). Sporadic ALS (sALS) accounts for 90% of cases and has no clear etiology, while familial ALS (fALS) accounts for 10% of cases and contains an underlying genetic component. However, while these two forms differ in causation, they appear pathologically and clinically indistinguishable. There is no known cure for ALS. There are two approved medications to treat ALS, riluzole (a glutamate blocker) and edaravone (a free radical scavenger), but with limited efficacy. Riluzole, approved in 1995, is administered orally twice daily and delays time to tracheostomy or death in patients with ALS (Riluzole package insert 2016), prolonging survival by 2-3 months (Miller et al. 2012). Edaravone, approved in the US in 2017, is administered in courses intravenously and shows efficacy in only a small subset of patients with ALS.

Recent research by the group and others indicates that boosting the activity of the histone deacetylate enzymes known as sirtuins, via a combination of nicotinamide riboside (NR) and pterostilbene, has neuroprotective effects in ALS and may delay clinical disease progression.

Based on these preliminary findings, the group hypothesized that oral administration of combination therapy with NR and pterostilbene will inhibit neurodegeneration and increase survival and quality of life in patients with ALS. To test this hypothesis, they are now running a phase-II, multi-centre, double-blinded randomized clinical trial of oral NR and pterostilbene in early ALS (NO-ALS study). Based on their power estimates, a total of 180 patients will be recruited from all over Norway. The study was started in October 2020. By end of February 2021, 20 patients are included in the study. All study centres will be recruiting by end of March 2021.

This novel project has the potential to discover a therapy, modulating disease activity and progression in ALS, thus vastly improving patient care and prognosis. The study has received support from Helse Vest and KLINBEFORSK.

Selected Key Publications

1. Association of SNCA Parkinson’s Disease Risk Polymorphisms With Disease Progression in Newly Diagnosed Patients. Szwedo AA, Pedersen CC, Ushakova A, Forsgren L, Tysnes OB, Counsell CE, Alves G, Lange J, Macleod AD, Maple-Grødem J. Front Neurol. 2021 Feb 10;11:620585. doi: 10.3389/fneur.2020.620585. eCollection 2020.PMID: 33643180 Free PMC article.
2. Letter to the editor in response to the letter from the EPIPARK Study Group regarding the publication ‘Progression of fatigue in Parkinson’s disease – a 9-year follow-up’ (Eur J Neurol 2021. doi:10.1111/ene.14520). Ongre SO, Dalen I, Tysnes OB, Alves G, Herlofson K.Eur J Neurol. 2021 Feb 5. doi: 10.1111/ene.14765. Online ahead of print.PMID: 33547699
3. Association of GBA Genotype With Motor and Functional Decline in Patients With Newly Diagnosed Parkinson Disease. MapleGrødem J, Dalen I, Tysnes OB, Macleod AD, Forsgren L, Counsell CE, Alves G.Neurology. 2021 Feb 16;96(7):e1036-e1044. doi: 10.1212/WNL.0000000000011411. Epub 2020 Dec 21.PMID: 33443131
4. Differential transcript usage in the Parkinson’s disease brain. Dick F, Nido GS, Alves GW, Tysnes OB, Nilsen GH, Dölle C, Tzoulis C.PLoS Genet. 2020 Nov 2;16(11):e1009182. doi: 10.1371/journal.pgen.1009182. eCollection 2020 Nov.PMID: 33137089 Free PMC article.
5. Differences in the Presentation and Progression of Parkinson’s Disease by Sex. Iwaki H, Blauwendraat C, Leonard HL, Makarious MB, Kim JJ, Liu G, Maple-Grødem J, Corvol JC, Pihlstrøm L, van Nimwegen M, Smolensky L, Amondikar N, Hutten SJ, Frasier M, Nguyen KH, Rick J, Eberly S, Faghri F, Auinger P, Scott KM, Wijeyekoon R, Van Deerlin VM, Hernandez DG, Gibbs RJ, Day-Williams AG, Brice A, Alves G, Noyce AJ, Tysnes OB, Evans JR, Breen DP, Estrada K, Wegel CE, Danjou F, Simon DK, Andreassen OA, Ravina B, Toft M, Heutink P, Bloem BR, Weintraub D, Barker RA, Williams-Gray CH, van de Warrenburg BP, Van Hilten JJ, Scherzer CR, Singleton AB, Nalls MA.Mov Disord. 2021 Jan;36(1):106-117. doi: 10.1002/mds.28312. Epub 2020 Oct 1.PMID: 33002231
6. Meta-analysis of whole-exome sequencing data from two independent cohorts finds no evidence for rare variant enrichment in Parkinson disease associated loci. Gaare JJ, Nido G, Dölle C, Sztromwasser P, Alves G, Tysnes OB, Haugarvoll K, Tzoulis C.PLoS One. 2020 Oct 1;15(10):e0239824. doi: 10.1371/journal.pone.0239824. eCollection 2020.PMID: 33002040 Free PMC article.
7. Progression of fatigue in Parkinson’s disease – a 9-year follow-up. Ongre SO, Dalen I, Tysnes OB, Alves G, Herlofson K.Eur J Neurol. 2021 Jan;28(1):108-116. doi: 10.1111/ene.14520. Epub 2020 Oct 16.PMID: 32920893
8. Genetic risk scores and hallucinations in patients with Parkinson disease. Kusters CDJ, Paul KC, Duarte Folle A, Keener AM, Bronstein JM, Dobricic V, Tysnes OB, Bertram L, Alves G, Sinsheimer JS, Lill CM, Maple-Grødem J, Ritz BR.Neurol Genet. 2020 Jul 20;6(5):e492. doi: 10.1212/NXG.0000000000000492. eCollection 2020 Oct.PMID: 32802953 Free PMC article.
9. Impulsive and compulsive behaviors in Parkinson’s disease: Impact on quality of and satisfaction with life, and caregiver burden. Erga AH, Alves G, Tysnes OB, Pedersen KF.Parkinsonism Relat Disord. 2020 Sep;78:27-30. doi: 10.1016/j. parkreldis.2020.07.007. Epub 2020 Jul 9.PMID: 32679528 Free article.
10. Validation of a UPDRS-/MDS-UPDRS-based definition of functional dependency for Parkinson’s disease. Ramsay N, Macleod AD, Alves G, Camacho M, Forsgren L, Lawson RA, Maple-Grødem J, Tysnes OB, Williams-Gray CH, Yarnall AJ, Counsell CE; Parkinson’s Incidence Cohorts Collaboration; PINE Study; CamPaIGN study; PICNICS study; NYPUM Study; ParkWest Study: ParkWest Principal investigators; Study personnel; ICICLE-PD Study.Parkinsonism Relat Disord. 2020 Jul;76:49-53. doi:10.1016/j.parkreldis.2020.05.034. Epub 2020 May 30.PMID: 32645619
11. Common gene expression signatures in Parkinson’s disease are driven by changes in cell composition. Nido GS, Dick F, Toker L, Petersen K, Alves G, Tysnes OB, Jonassen I, Haugarvoll K, Tzoulis C.Acta Neuropathol Commun. 2020 Apr 21;8(1):55. doi: 10.1186/s40478-020-00932-7.PMID: 32317022 Free PMC article.
12. Targeting NAD+ in translational research to relieve diseases and conditions of metabolic stress and ageing. Gilmour BC, Gudmundsrud R, Frank J, Hov A, Lautrup S, Aman Y, Røsjø H, Brenner C, Ziegler M, Tysnes OB, Tzoulis C, Omland T, Søraas A, Holmøy T, Bergersen LH, Storm-Mathisen J, Nilsen H, Fang EF.Mech Ageing Dev. 2020 Mar;186:111208. doi: 10.1016/j. mad.2020.111208. Epub 2020 Jan 15.PMID: 31953124 Review.
13. Evolution of impulsive-compulsive behaviors and cognition in Parkinson’s disease. Erga AH, Alves G, Tysnes OB, Pedersen KF.J Neurol. 2020 Jan;267(1):259-266. doi: 10.1007/s00415-019-09584-7. Epub 2019 Oct 18.PMID: 31628533 Free PMC article.

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