Evaluation of Essential Metal Metabolism (META-GCA)

Evaluation of Essential Metal Metabolism in Patients With Disorders of Consciousness

Disturbance of consciousness (DoC) is a state in which consciousness is altered following brain damage and can manifest in several conditions that result from the loss of regulation of the neural function of the two components of consciousness, alertness and awareness.

It is known that the main causes of disorders of consciousness have important effects on the disruption of essential metal homeostasis.

In particular, myocardial infarction and heart failure, ischemic and hemorrhagic stroke and head trauma trigger phenomena of diffuse axonal damage, hypoxia and re-perfusion that profoundly alter the metabolism of cerebral O2 that reacts with essential metals , in Fenton-type reactions whose predominant effect is an extensive production of reactive oxygen species (ROS) and pro-oxidant molecules.

Fe, Cu and zinc (Zn) are essential metals for life: two thirds of the proteins in our body use these metals that play a crucial role as catalysts or structural elements of proteins in various biological processes, such as cellular respiration in mitochondria, the production and maturation of red and white blood cells, the elasticity of connective tissue, the production of myelin and the production of some neurotransmitters. For this reason, the biology of essential metals has a major impact on our health and the disruption of their homeostasis inexorably leads to disease.

These metals are very important for the metabolism of the Central Nervous System (CNS) and Cu, in particular, even in adults, is involved in the production of myelin and in the production of some neurotransmitters of the diffuse modulatory systems . Cu is a cofactor of the enzymes dopamine β-hydroxylase, and monoamine oxidase involved in the balance of catecholamines , and is altered in some disorders of Cu metabolism.

Study Overview

• Status: Active, not recruiting
• Conditions: Disturbance of Consciousness; Alteration of Metabolism; Essential Metals
• Intervention / Treatment: Other: peripheral venous blood samples, these will be performed in order to measure the biological markers in the serum

• Study Type: Observational
• Enrollment (Actual): 120

Contacts and Locations

Study Locations

• Italy
  • RM
    • Roma, RM, Italy, 00168
      • UOC Neuroriabilitazione ad alta intensità , Policlinico "A. Gemelli"

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients of both sexes with DoC being treated at the U.O.C. of High Intensity Neurorehabilitation, Fondazione Policlinico Universitario Gemelli IRCCS of Rome

Description

Inclusion Criteria:

• Patients who have been in a coma state, documented with a GCS ≤ 8 for at least 24 hours;

  • Presence of a disturbance of consciousness, identified through the Coma Recovery Scale-revised (CRS-r) and classified as coma, vegetative state or minimally conscious state;
  • Latency of the acute event between 15 days and 6 months;
  • Ability of the caregiver/guardian to understand and sign the informed consent.

Exclusion Criteria:

• Age <18 years;

  • Psychiatric or other pathologies;
  • Inflammatory state related to ongoing infections;
  • Refusal or inability to sign the written informed consent to participate in the study.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Experimental: Gruop A; Difference in metal concentrations (7 metals) in GCA subjects compared to those in previously acquired sera of healthy controls.	Other: peripheral venous blood samples, these will be performed in order to measure the biological markers in the serum; peripheral venous blood samples, these will be performed in order to measure the biological markers in the serum
Experimental: Group B: Differences and Correlation; Differences in essential metal concentrations at 30 days compared to baseline in GCA patients.; Baseline differences in essential metal metabolism in subcategories of patients with impaired consciousness (coma/VS vs MCS, traumatic brain injury vs non-traumatic brain injury).; Correlation between clinical scales and essential metal metabolism	Other: peripheral venous blood samples, these will be performed in order to measure the biological markers in the serum; peripheral venous blood samples, these will be performed in order to measure the biological markers in the serum

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood concetration of essential metal in patients with acquired brain injury	Quantification of blood essential metal levels in peripheral venous blood samples in patients with acquired brain injury (Fe, range: Men: 65-178 µg/dL, Women: 50-170 µg/dL; Zn, range: 75- 110 µg/dL; Cu, range: Men: 60-160 µg/dL, Women: 80-155 µg/dL;non-Cp Cu, range: less than 5 µg/dL) compared to healthy patients.	Changes from baseline (T0), after 30 days of treatment (T1)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in essential metal blood concentration in subcategories of patients with impaired consciousness	Baseline differences in essential metal metabolism in subcategories of patients with disturbance of consciousness (coma/VS vs MCS using CRS-r scale range: 0 to 23).	At baseline (T0) and 30 days (T1)
Differences in essential metal blood concentration in subcategories of patients with acquired brain injury (traumatic vs non-traumatic)	Baseline differences in essential metal blood concentration in subcategories of patients with acquired brain injury ( etiology: traumatic vs non-traumatic).	At baseline (T0) and 30 days (T1)
Correlation between clinical outcome related to autonomy and disability and essential metal blood concentration	The clinical evaluation will be carried out using the following evaluation scales: Barthel Index (mBI) (range 0 to 100), the Disability Rating Scale (DRS) (range 0 to 29). As regards peripheral venous blood sampling, these will be performed in order to measure the following biological markers on serum: Fe, range men 65 and 178 µg/dL, women 50 and 170 µg/dL; Zn, range 75 -110 µg/dL; Cu, range men 60-160 µg/dL, women: 80-155 µg/dL; Ferr, range men 20-200 ng/mL, women 20-120 ng/mL; Tf, range men: 215-365 mg/dL, women: 250-380 mg/dL; Cp, range 20-50 mg/dL: Non-Cp Cu, range less than 5 µg/dL.	At baseline (T0) and 30 days (T1)
Correlation between clinical outcome related to motor performance and essential metal blood concentration	The clinical evaluation will be carried out using the following evaluation scales: Motricity Index (range 0 to 100 points). As regards peripheral venous blood sampling, these will be performed in order to measure the following biological markers on serum: Fe, range men 65 and 178 µg/dL, women 50 and 170 µg/dL; Zn, range 75 -110 µg/dL; Cu, range men 60-160 µg/dL, women: 80-155 µg/dL; Ferr, range men 20-200 ng/mL, women 20-120 ng/mL; Tf, range men: 215-365 mg/dL, women: 250-380 mg/dL; Cp, range 20-50 mg/dL: Non-Cp Cu, range less than 5 µg/dL.	At baseline (T0) and 30 days (T1)
Correlation between clinical outcome related to state of consciousness and cognitive level and essential metal blood concentration	The clinical evaluation will be carried out using the following evaluation scales: Coma Recovery Scale - Journal (CRS-r) (range 0 to 23), the Level of Cognitive Functioning (LCF) (range10 levels) and the Full Outline of UnResponsiveness (FOUR-Score) (range 0 to 16). As regards peripheral venous blood sampling, these will be performed in order to measure the following biological markers on serum: Fe, range men 65 and 178 µg/dL, women 50 and 170 µg/dL; Zn, range 75 -110 µg/dL; Cu, range men 60-160 µg/dL, women: 80-155 µg/dL; Ferr, range men 20-200 ng/mL, women 20-120 ng/mL; Tf, range men: 215-365 mg/dL, women: 250-380 mg/dL; Cp, range 20-50 mg/dL: Non-Cp Cu, range less than 5 µg/dL.	At baseline (T0) and 30 days (T1)

Collaborators and Investigators

• Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Investigators: Study Chair: Stefano mr Bonomi, MD,, Fondazione Policlinico Universitario A. Gemelli, IRCCS

Publications and helpful links

General Publications

• Laureys S, Celesia GG, Cohadon F, Lavrijsen J, Leon-Carrion J, Sannita WG, Sazbon L, Schmutzhard E, von Wild KR, Zeman A, Dolce G; European Task Force on Disorders of Consciousness. Unresponsive wakefulness syndrome: a new name for the vegetative state or apallic syndrome. BMC Med. 2010 Nov 1;8:68. doi: 10.1186/1741-7015-8-68.
• Giacino JT, Kalmar K. Diagnostic and prognostic guidelines for the vegetative and minimally conscious states. Neuropsychol Rehabil. 2005 Jul-Sep;15(3-4):166-74. doi: 10.1080/09602010443000498.
• Grassi M, Palluzzi F, Tarantino B. SEMgraph: an R package for causal network inference of high-throughput data with structural equation models. Bioinformatics. 2022 Oct 14;38(20):4829-4830. doi: 10.1093/bioinformatics/btac567.
• Nicoletti VG, Pajer K, Calcagno D, Pajenda G, Nogradi A. The Role of Metals in the Neuroregenerative Action of BDNF, GDNF, NGF and Other Neurotrophic Factors. Biomolecules. 2022 Jul 22;12(8):1015. doi: 10.3390/biom12081015.
• Squitti R, Ventriglia M, Simonelli I, Bonvicini C, Costa A, Perini G, Binetti G, Benussi L, Ghidoni R, Koch G, Borroni B, Albanese A, Sensi SL, Rongioletti M. Copper Imbalance in Alzheimer's Disease: Meta-Analysis of Serum, Plasma, and Brain Specimens, and Replication Study Evaluating ATP7B Gene Variants. Biomolecules. 2021 Jun 29;11(7):960. doi: 10.3390/biom11070960.
• Squitti R, Faller P, Hureau C, Granzotto A, White AR, Kepp KP. Copper Imbalance in Alzheimer's Disease and Its Link with the Amyloid Hypothesis: Towards a Combined Clinical, Chemical, and Genetic Etiology. J Alzheimers Dis. 2021;83(1):23-41. doi: 10.3233/JAD-201556.
• Cheng L, Cortese D, Monti MM, Wang F, Riganello F, Arcuri F, Di H, Schnakers C. Do Sensory Stimulation Programs Have an Impact on Consciousness Recovery? Front Neurol. 2018 Oct 2;9:826. doi: 10.3389/fneur.2018.00826. eCollection 2018.
• Squitti R, Reale G, Tondolo V, Crescenti D, Bellini S, Moci M, Caliandro P, Padua L, Rongioletti M. Imbalance of Essential Metals in Traumatic Brain Injury and Its Possible Link with Disorders of Consciousness. Int J Mol Sci. 2023 Apr 6;24(7):6867. doi: 10.3390/ijms24076867.
• Dolce G, Lucca LF, Riganello F, Arcuri F, Quintieri M, Cortese MD, Pignolo L. Advances in the neurorehabilitation of severe disorder of consciousness. Ann Ist Super Sanita. 2014;50(3):234-40. doi: 10.4415/ANN_14_03_06.
• von Wild K, Laureys ST, Gerstenbrand F, Dolce G, Onose G. The vegetative state--a syndrome in search of a name. J Med Life. 2012 Feb 22;5(1):3-15. Epub 2012 Mar 5.
• Davis T, Ings A; National Institute of Health and Care Excellence. Head injury: triage, assessment, investigation and early management of head injury in children, young people and adults (NICE guideline CG 176). Arch Dis Child Educ Pract Ed. 2015 Apr;100(2):97-100. doi: 10.1136/archdischild-2014-306797. Epub 2014 Oct 21. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): March 17, 2025
• Primary Completion (Estimated): March 31, 2026
• Study Completion (Estimated): March 31, 2027

Study Registration Dates

• First Submitted: March 17, 2025
• First Submitted That Met QC Criteria: March 28, 2025
• First Posted (Actual): April 4, 2025

Study Record Updates

• Last Update Posted (Actual): April 9, 2025
• Last Update Submitted That Met QC Criteria: April 8, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: patients with disturbance of consciousness; essential metal; metabolism status
• Other Study ID Numbers: 6279

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No