Longitudinal Assessment of Autonomic and Sensory Nervous System in ALS

Overview

The goal of this interventional non-pharmacological study is to evaluate, using a multimodal approach, the progression of autonomic and sensory involvement in in amyotrophic lateral sclerosis (ALS) patients enrolled within 18 months from motor onset and its relationship with the progression of overall clinical disability. The main questions it aims to answer are: * Is autonomic dysfunction at diagnosis associated with disease progression and survival in patients with Amyotrophic Lateral Sclerosis ? * Can we identify in the skin biomarkers to be used as reliable measures of disease progression and to apply in future clinical trials for patient stratification and to assess response to drug treatment ? Participants at time 0 will receive a full clinical and instrumental examination and a blood sample testing to check inclusion and exclusion criteria, genetic screening for the most common genes associated with ALS (SOD1, FUS, TARDBP and c9orf72), questionnaires about clinical characteristics, quality of life, pain and a multidomain battery of neuropsychological tests, multimodal assessment of the autonomic nervous system including skin biopsy for morphological study. At follow-up we'll perform clinical scales and skin biopsy. Researchers will compare results from ALS patients with data obtained from a population of age and sex matched healthy subjects.

Interventions

• Diagnostic test Skin biopsy
  A punch skin biopsy of 3mm will be used to analyze cutaneous innervation
• Diagnostic test Cardiovascular Reflexes testing
  Cardiovascular reflex tests including deep breathing, head-up Tilt, standing, isometric exercises, mental arithmetic and Valsalva maneuver.
• Diagnostic test Administration of clinical scales evaluating autonomic symptoms, pain small fiber neuropathy symptoms
  We'll characterize patients' symptoms through the administration of clinical scales such as: SCOPA-AUT autonomic symptoms scale; Brief Pain Inventory questionnaire
• Diagnostic test Dinamic Sweat Test
  Test for the functional assessment of postganglionic sudomotor pathway

Primary outcome measures

• Sensory peripheral innervation (IENF) [Time frame: At recruitment]
• Autonomic peripheral innervation [Time frame: At recruitment]
• Autonomic peripheral innervation [Time frame: At follow-up, an average of 6 months]
• Sensory peripheral innervation (IENF) [Time frame: At follow-up, an average of 6 months]

Secondary outcome measures (4)

• Sensory and autonomic symptoms evaluated by clinical scales [Time frame: At the recruitment]
• Sensory and autonomic symptoms evaluated by clinical scales [Time frame: At follow-up, an average of 6 months]
• Assessment of Cardiovascular function [Time frame: baseline]
• Sudomotor function [Time frame: baseline]

Eligibility criteria

Inclusion criteria

• ALS patients will be recruited within 18 months from the motor symptoms onset

Exclusion criteria

• glucose intolerance or conditions potentially affecting the peripheral nervous system

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Basic science

Study locations

Italy · 2 centers

• ICS Maugeri - IRCCS of Telese Terme — Telese Terme
• Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Na — Naples

Publications

• Mahoney CJ, Ahmed RM, Huynh W, Tu S, Rohrer JD, Bedlack RS, Hardiman O, Kiernan MC. Pathophysiology and Treatment of Non-motor Dysfunction in Amyotrophic Lateral Sclerosis. CNS Drugs. 2021 May;35(5):483-505. doi: 10.1007/s40263-021-00820-1. Epub 2021 May 15. PMID 33993457
• Gentile F, Scarlino S, Falzone YM, Lunetta C, Tremolizzo L, Quattrini A, Riva N. The Peripheral Nervous System in Amyotrophic Lateral Sclerosis: Opportunities for Translational Research. Front Neurosci. 2019 Jun 25;13:601. doi: 10.3389/fnins.2019.00601. eCollection 2019. PMID 31293369
• Sassone J, Taiana M, Lombardi R, Porretta-Serapiglia C, Freschi M, Bonanno S, Marcuzzo S, Caravello F, Bendotti C, Lauria G. ALS mouse model SOD1G93A displays early pathology of sensory small fibers associated to accumulation of a neurotoxic splice variant of peripherin. Hum Mol Genet. 2016 Apr 15;25(8):1588-99. doi: 10.1093/hmg/ddw035. Epub 2016 Feb 9. PMID 26908600
• Weis J, Katona I, Muller-Newen G, Sommer C, Necula G, Hendrich C, Ludolph AC, Sperfeld AD. Small-fiber neuropathy in patients with ALS. Neurology. 2011 Jun 7;76(23):2024-9. doi: 10.1212/WNL.0b013e31821e553a. PMID 21646630
• Truini A, Biasiotta A, Onesti E, Di Stefano G, Ceccanti M, La Cesa S, Pepe A, Giordano C, Cruccu G, Inghilleri M. Small-fibre neuropathy related to bulbar and spinal-onset in patients with ALS. J Neurol. 2015;262(4):1014-8. doi: 10.1007/s00415-015-7672-0. Epub 2015 Feb 17. PMID 25683764
• Nolano M, Provitera V, Manganelli F, Iodice R, Caporaso G, Stancanelli A, Marinou K, Lanzillo B, Santoro L, Mora G. Non-motor involvement in amyotrophic lateral sclerosis: new insight from nerve and vessel analysis in skin biopsy. Neuropathol Appl Neurobiol. 2017 Feb;43(2):119-132. doi: 10.1111/nan.12332. Epub 2016 Jul 7. PMID 27288647
• deCarvalho M, Gromicho M, Andersen P, Grosskreutz J, Kuzma-Kozakiewicz M, Petri S, Uysal H, Pinto S. Peripheral neuropathy in ALS: phenotype association. J Neurol Neurosurg Psychiatry. 2021 Oct;92(10):1133-1134. doi: 10.1136/jnnp-2020-325164. Epub 2020 Dec 28. No abstract available. PMID 33372053
• Chio A, Mora G, Lauria G. Pain in amyotrophic lateral sclerosis. Lancet Neurol. 2017 Feb;16(2):144-157. doi: 10.1016/S1474-4422(16)30358-1. Epub 2016 Dec 8. PMID 27964824

Identifiers

NCT: NCT05747937 · SBLAB/SLA20

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗