Research Studies

Study Title

Pre-fALS (Pre-Symptomatic Familial ALS Study)

Enrollment Status

Recruiting

Principal Investigators

Michael Benatar, MD, PhD and Joanne Wuu, ScM

Study Type

Observational

Goals

Characterize the pre-symptomatic phase of ALS Develop biomarkers that may be used to predict when symptomatic disease will emerge Prepare for early intervention and disease prevention clinical trials

Enrolling

Pre-symptomatic mutation carriers

Eligibility

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Age 18+
Unaffected individuals who may be at genetic risk for ALS
Genetic cause of ALS in the family is known
Living in the U.S. or Canada
Willing/able to travel to UMiami for in-person study visits every 1-2 years and comply with other study procedures

Study Involvement

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Screening and eligibility determination (via phone)
Genetic testing (with choice of learning the results or not)
Genetic counseling
Regular (every 1-2 years) visits to UMiami for 2-3 days

  • Neurological exam, including EMG
  • Blood, urine, and (optional) CSF collection
  • Breathing test
  • Fine motor skills testing
  • MRI (optional)
  • Neuropsychological assessment
  • Family and medical history review
  • Environmental exposure review & surveys

Regular (every 3-4 months) assessments, via telephone calls or remote visits comprising questionnaires and blood & urine collection

Primary Funding Source

NIH

Related Publications

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Benatar M, Granit V, Andersen PM, Grignon AL, McHutchison C, Cosentino S, Malaspina A, Wuu J. Mild motor impairment as prodromal state in amyotrophic lateral sclerosis: a new diagnostic entity. Brain. 2022 May 20:awac185. Online ahead of print.

https://pubmed.ncbi.nlm.nih.gov/35594156

Benatar M, Wuu J, Andersen PM, Bucelli RC, Andrews JA, Otto M, Farahany NA, Harrington EA, Chen W, Mitchell AA, Ferguson T, Chew S, Gedney L, Oakley S, Heo J, Chary S, Fanning L, Graham D, Sun P, Liu Y, Wong J, Fradette S. Design of a randomized, placebo-controlled, phase 3 trial of tofersen initiated in clinically presymptomatic SOD1 variant carriers: the ATLAS Study. Neurotherapeutics. 2022 May 18. Online ahead of print.

https://pubmed.ncbi.nlm.nih.gov/35585374

McMillan CT, Wuu J, Rascovsky K, Cosentino S, Grossman M, Elman L, Quinn C, Rosario L, Stark JH, Granit V, Briemberg H, Chenji S, Dionne A, Genge A, Johnston W, Korngut L, Shoesmith C, Zinman L; Canadian ALS Neuroimaging Consortium (CALSNIC), Kalra S, Benatar M. Defining cognitive impairment in amyotrophic lateral sclerosis: an evaluation of empirical approaches. Amyotroph Lateral Scler Frontotemporal Degener. 2022 Mar 7:1-10. Online ahead of print.

https://pubmed.ncbi.nlm.nih.gov/35253557

Benatar M, Wuu J, McHutchison C, Postuma RB, Boeve BF, Petersen R, Ross CA, Rosen H, Arias JJ, Fradette S, McDermott MP, Shefner J, Stanislaw C, Abrahams S, Cosentino S, Andersen PM, Finkel RS, Granit V, Grignon AL, Rohrer JD, McMillan CT, Grossman M, Al-Chalabi A, Turner MR; attendees of the First International Pre-Symptomatic ALS Workshop. Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases. Brain. 2021 Oct 22. Online ahead of print.

https://pubmed.ncbi.nlm.nih.gov/34677606

Gray E, Thompson AG, Wuu J, Pelt J, Talbot K, Benatar M, Turner MR. CSF chitinases before and after symptom onset in amyotrophic lateral sclerosis. Ann Clin Transl Neurol. 2020 Aug;7(8):1296-1306. Epub 2020 Jul 14.

https://pubmed.ncbi.nlm.nih.gov/32666680

Benatar M, Wuu J, Lombardi V, Jeromin A, Bowser R, Andersen PM, Malaspina A. Neurofilaments in pre-symptomatic ALS and the impact of genotype. Amyotroph Lateral Scler Frontotemporal Degener. 2019 Nov;20(7-8):538-548. Epub 2019 Aug 21.

https://pubmed.ncbi.nlm.nih.gov/31432691

Gertsman I, Wuu J, McAlonis-Downes M, Ghassemian M, Ling K, Rigo F, Bennett F, Benatar M, Miller TM, Da Cruz S. An endogenous peptide marker differentiates SOD1 stability and facilitates pharmacodynamic monitoring in SOD1 amyotrophic lateral sclerosis. JCI Insight. 2019 May 16;4(10):e122768.

https://pubmed.ncbi.nlm.nih.gov/31092730

Benatar M, Turner MR, Wuu J. Defining pre-symptomatic amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2019 Aug;20(5-6):303-309. Epub 2019 Mar 20.

https://pubmed.ncbi.nlm.nih.gov/30892087

Benatar M, Wuu J, Andersen PM, Lombardi V, Malaspina A. Neurofilament light: A candidate biomarker of presymptomatic amyotrophic lateral sclerosis and phenoconversion. Ann Neurol. 2018 Jul;84(1):130-139. Epub 2018 Aug 16.

https://pubmed.ncbi.nlm.nih.gov/30014505

Proudfoot M, van Ede F, Quinn A, Colclough GL, Wuu J, Talbot K, Benatar M, Woolrich MW, Nobre AC, Turner MR. Impaired corticomuscular and interhemispheric cortical beta oscillation coupling in amyotrophic lateral sclerosis. Clin Neurophysiol. 2018 Jul;129(7):1479-1489. Epub 2018 Apr 6.

https://pubmed.ncbi.nlm.nih.gov/29678369

Proudfoot M, Colclough GL, Quinn A, Wuu J, Talbot K, Benatar M, Nobre AC, Woolrich MW, Turner MR. Increased cerebral functional connectivity in ALS: A resting-state magnetoencephalography study. Neurology. 2018 Apr 17;90(16):e1418-e1424. Epub 2018 Mar 21.

https://pubmed.ncbi.nlm.nih.gov/29661904

Nordin A, Akimoto C, Wuolikainen A, Alstermark H, Forsberg K, Baumann P, Pinto S, de Carvalho M, Hübers A, Nordin F, Ludolph AC, Weishaupt JH, Meyer T, Grehl T, Schweikert K, Weber M, Burkhardt C, Neuwirth C, Holmøy T, Morita M, Tysnes OB, Benatar M, Wuu J, Lange DJ, Bisgård C, Asgari N, Tarvainen I, Brännström T, Andersen PM. Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study. Amyotroph Lateral Scler Frontotemporal Degener. 2017 May;18(3-4):256-264. Epub 2016 Dec 12.

https://pubmed.ncbi.nlm.nih.gov/27936955

Proudfoot M, Rohenkohl G, Quinn A, Colclough GL, Wuu J, Talbot K, Woolrich MW, Benatar M, Nobre AC, Turner MR. Altered cortical beta-band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis. Hum Brain Mapp. 2017 Jan;38(1):237-254. Epub 2016 Sep 13.

https://pubmed.ncbi.nlm.nih.gov/27623516

Benatar M, Stanislaw C, Reyes E, Hussain S, Cooley A, Fernandez MC, Dauphin DD, Michon SC, Andersen PM, Wuu J. Presymptomatic ALS genetic counseling and testing: Experience and recommendations. Neurology. 2016 Jun 14;86(24):2295-302. Epub 2016 May 18.

https://pubmed.ncbi.nlm.nih.gov/27194384

Menke RA, Proudfoot M, Wuu J, Andersen PM, Talbot K, Benatar M, Turner MR. Increased functional connectivity common to symptomatic amyotrophic lateral sclerosis and those at genetic risk. J Neurol Neurosurg Psychiatry. 2016 Jun;87(6):580-8. Epub 2016 Jan 5.

https://pubmed.ncbi.nlm.nih.gov/26733601

Benatar M, Wuu J, Ravits J. Opportunity and innovation in studying pre-symptomatic amyotrophic lateral sclerosis. Muscle Nerve. 2013 May;47(5):629-31. Epub 2013 Mar 15.

https://pubmed.ncbi.nlm.nih.gov/23494825

Benatar M, Wuu J. Presymptomatic studies in ALS: rationale, challenges, and approach. Neurology. 2012 Oct 16;79(16):1732-9.

https://pubmed.ncbi.nlm.nih.gov/23071166

Carew JD, Nair G, Andersen PM, Wuu J, Gronka S, Hu X, Benatar M. Presymptomatic spinal cord neurometabolic findings in SOD1-positive people at risk for familial ALS. Neurology. 2011 Oct 4;77(14):1370-5. Epub 2011 Sep 21.

https://pubmed.ncbi.nlm.nih.gov/21940617

Fanos JH, Gronka S, Wuu J, Stanislaw C, Andersen PM, Benatar M. Impact of presymptomatic genetic testing for familial amyotrophic lateral sclerosis. Genet Med. 2011 Apr;13(4):342-8.

https://pubmed.ncbi.nlm.nih.gov/21285887

Nair G, Carew JD, Usher S, Lu D, Hu XP, Benatar M. Diffusion tensor imaging reveals regional differences in the cervical spinal cord in amyotrophic lateral sclerosis. Neuroimage. 2010 Nov 1;53(2):576-83. Epub 2010 Jun 28.

https://pubmed.ncbi.nlm.nih.gov/20600964

Related Presentations & Lectures

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Gray E (presenter), AG Thompson, Wuu J, Pelt J, Talbot K, Benatar M, Turner MR. Chitotriosidase level and activity rises in the pre- and early symptomatic phases of ALS. Platform presentation at the 30th International Symposium on ALS/MND, Perth, Australia, Dec 4-6, 2019.

McMillan CT (presenter), Wuu J, Cook P, Olm C, Duda J, Gee J, Clayman CE, Elman L, McCluskey L, Irwin DJ, Grossman M, Benatar M. Baseline and longitudinal volumetric changes associated with presymptomatic C9ORF72 repeat expansion carriers. Platform presentation at the 29th International Symposium on ALS/MND, Glassgow, UK, Dec 7-9, 2018.

Benatar M (presenter), Wuu J, Lombardi V, Jeromin A, Bowser R, Andersen PM, Malaspina A. When does ALS begin? Insights from serum and CSF neurofilament light and heavy. Platform presentation at the 29th International Symposium on ALS/MND, Glassgow, UK, Dec 7-9, 2018.

Benatar M (presenter), Wuu J, Lombardi V, Andersen PM, Malaspina A. Blood and CSF neurofilament levels as biomarkers of pre-symptomatic disease. Platform presentation at the 28th International Symposium on ALS/MND, Boston, MA, Dec 8-10, 2017.

Benatar M (presenter), Reilmann R, Schubert R, Reyes E, Seleski C, Cooley A, Wuu J. Quantitative Motor Testing: Biomarker of Pre-Symptomatic ALS? Platform presentation at the 27th International Symposium on ALS/MND, Dublin, Ireland, Dec 7-9, 2016.

Benatar M (presenter), Stanislaw C, Reye E, Hussain S, Andersen PM, Wuu J. Pre-Symptomatic ALS genetic counseling and testing: Experience and recommendations. Platform presentation at the 26th International Symposium on ALS/MND, Orlando, FL, Dec 11-13, 2015.

Benatar M (invited speaker). The challenge of early therapeutic intervention in ALS. Invited presentation at the 25th International ALS/MND Meeting. Brussels, Belgium, December 2014.

Nair G, Wuu J, Gronka S, Walker M, Carew J, Benatar M (presenter). MRI evidence of disease in pre-symptomatic SOD1+ individuals at risk for developing familial ALS. Platform presentation at the 22nd International Symposium on ALS/MND, Sydney, Australia, Nov 30 - Dec 2, 2011.

Gronka S, Walker M, Wuu J, Stanislaw C, Fanos J, Atassi N, Jaffa M, Andersen P, Cudkowicz M, Benatar M (presenter). Telemedicine to facilitate ALS research. Platform presentation at the 21st International Symposium on ALS/MND, Orlando, FL, Dec 11-13, 2010.

Gronka S, Wuu J, Usher S, Polak M, Benatar M (presenter). Tackling the challenges of ALS from a familial perspective. Platform presentation at the 20th International Symposium on ALS/MND, Berlin, Germany, Dec 4-10, 2009.

McMillan CT (presenter), Wuu J, Hennessy L, Placek K, Clinical Research in ALS (CRiALS) Study, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Canadian ALS Neuroimaging Consortium (CALSNIC), Quinn C, Elman L, Grossman M, Rampersaud E, Wu G, Taylor JP, Kalra S, Benatar M. Frequency, hazard, and genetic risk factors of cognitive impairment in amyotrophic lateral sclerosis (ALS). Invited presentation at the International Neuropsychological Society Annual Meeting (virtual), Feb 2-5, 2021.

Benatar M (invited speaker). Biomarkers for ALS therapy development. Seminar at the Technical Univeristy of Munich, Germany, Feb, 2021.

Benatar M (invited speaker). Symptomatic and pre-symptomatic biomarkers for ALS therapy development. Johns Hopkins ALS Clinical Trials Unit, Jan, 2021.

Benatar M (invited speaker). ALS Therapy Development. 44th Annual Jerome K Merlis Lectureship in Neuroscience. Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, October 2020.

Benatar M (presenter), Wuu J. Conceptual framework and strategies for studying pre-symptomatic ALS. 1st International Pre-Symptomatic ALS Workshop, Miami, FL, Jan 27, 2020.

Benatar M (invited speaker). Biomarkers for ALS Therapy Development. 5th Ottawa International Conference on Neuromuscular Disease and Biology. Ottawa, Canada, October 2019.

Benatar M (invited speaker). ALS Therapy Development: Challenges and Opportunities. Platform presentation at the International Conference on Neuromuscular Disease. Toronto, Canada, July 2016.

Benatar M (invited speaker). Lessons for Charcot-Marie Tooth (CMT) Clinical Trials from ALS Experience. Inherited Neuropathic Consortium Annual Meeting. Miami, FL, January 2016.

Benatar M (invited speaker). Challenges and Opportunities in ALS Therapy Development. Ottawa International Conference on Neuromuscular Biology, Disease and Therapy. Ottawa, Canada, September 2015.

Benatar M (invited speaker). Challenges and Opportunities in ALS Therapy Development. Flinders University Center for Neuroscience Seminar. Adelaide, Australia, September 2015.

Benatar M (invited speaker). Challenges and Opportunities in ALS Therapy Development. Congress on Motor and Cognitive Degenerative Diseases. Yachay, Ecuador, January 2015.

Benatar M (invited speaker). ALS Therapy Development: Challenges and Opportunities. ALS Association Wisconsin Chapter. Milwaukee, WI, May 2014.

Turner M (presenter), Filippini N, Govind V, Andersen PM, Stanislaw C, Reyes E, Hussain S, Wuu J, Benatar M. Pre-symptomatic loss of cerebral white matter integrity in those at genetic risk of amyotrophic lateral sclerosis. Platform presentation at the American Academy of Neurology 66th Annual Meeting, Philadelphia, PA, Apr 26 - May 3, 2014.

Benatar M (invited speaker). Pre-Symptomatic Studies in ALS: Rationale, Challenges and Approach. 12th Annual Packard Center Meeting. Baltimore, MD, March 2012.

Benatar M (invited speaker). Pre-fALS: Pre-Symptomatic Studies in ALS. Workshop on Biomarker Studies in Pre-Symptomatic Carriers of Familial ALS/FTD. University of Oxford, Oxford, UK, January 2012.

Benatar M (invited speaker). Identifying Biomarkers in Familial ALS. ALS Association Drug Discovery Meeting. Washington, DC, March 2012.

Benatar M (invited speaker). Piecing Together the Puzzle of ALS: An Emerging Picture. Beijing International Conference on Neurology. Beijing, China, June 2012.

Benatar M (invited speaker). Tackling the Challenges of ALS: A Familial Perspective. 2009 William L. Halseth ALS Visiting Lectureship. University of Colorado School of Medicine, Aurora, CO, February 2010.

Lu D, Rutkove S, Gronka S, Spieker A, Usher S, Wuu J, Andersen P, Benatar M (presenter). Electrical impedance myography (EIM) findings in pre-symptomatic SOD1+ subjects. Platform presentation at the Annual Northeast ALS Consortium Meeting, Washington, DC, Oct 27-29, 2010.

Benatar M (invited speaker). Lessons for Huntington’s Disease from Amyotrophic Lateral Sclerosis. World Huntington’s Conference. Vancouver, Canada, September 2009.

Benatar M (invited speaker). Piecing Together the Puzzle of ALS: An Emerging Picture. Visiting Professor and Guest Lecturer, South African Neurological Association Meeting. Johannesburg, South Africa, March 2009.

Benatar M (invited speaker). Predictive, Preventive and Therapeutic Studies in Familial ALS. ALS Association Annual Leadership Forum. Orange County, CA, January 2008.

Benatar M (invited speaker). Strategies for pre-symptomatic biomarker identification in familial ALS. Cold Spring Harbor Symposium on Drug Discovery, Biomarkers, and Clinical Trials for ALS. Banbury Center, Cold Spring Harbor, NY, September 2007.