ACE2 Gender Differences in Stroke With COVID-19

NCT04766645 | Completed

• 1 other identifier: FDG_Acegender_2021
• Study Type: observational
• Target: 77
• Locations: 1 country
• Sites: 1

Brief Summary

The new coronavirus SARS-CoV-2, causes the COVID-19 infection, which showed a form of neurovirulence involving the Central and peripheral Nervous Systems \[Baig et al, 2020\]. In a mouse model for human ACE2 expression, the virus entered the brain mainly through the olfactory bulb pathway \[Netland et al, 2008\], with an encephalic invasion uniformly lethal even with low viral doses and without lung involvement. The death of the animal was reasonably related to neuronal dysfunction/death in cardiorespiratory bone marrow centers, while the absence of ACE2 prevented severe encephalopathy. Men has a highly frequency of severe and lethal COVID-19, and the observed gender difference could be related to the regulation of ACE2 receptor expression. The ACE2 gene is encoded by a region of the X chromosome that escapes inactivation, so that women have an increased expression of this protein. The process of inactivation of the X chromosome includes DNA methylation with a decrease in the expression of genes that are affected by methylation. In This way an epigenetic mechanism could modulate the expression of ACE2 in a gender-specific way determining its levels and consequently its protective role. Also in this regulatory context of ACE2 expression the role of microRNA (miRNA) could be very important. In fact, the untranslated 3' region (UTR) of ACE2 presents a binding sequence for miRNA miR-200c-3p that has been found at high levels of expression in cellular models infected with H5N1 influenza virus \[Liu et al, 2017\]. In addition, high plasma levels of miR-200c-3p were found in patients with severe pneumonia while ACE2 was reduced suggesting a regulatory role of this miRNA in ACE2 receptor expression \[Liu et al, 2017\]. Deficiency of 25 (OH)D is common among elderly and obese men (during winter and spring), highlighting the sex-specific difference observed in COVID-19 infection \[La Vignera et al, 2020\]. This vitamin, envolved in physical recovery \[Siotto et al, 2019\], and in the pathway of the renin angiotensin system, seems important to be assessed in ex-COVID-19 patients with stroke outcomes in admission and at the end of the rehabilitation process. The study will consist in:

• Epigenetic study: evaluation of methylation of ACE2 promoter and miR-200c-3p levels.
• Biochemical analysis: the evaluation of levels of angiotensin II, ACE2 and Vitamin D.
• Correlation between rehabilitative outcome and biological markers

Conditions

Neurologic Manifestations

Keywords

Stroke; rehabilitation; ACE2; methylation; VitaminD

Outcome Measures

Primary Outcomes (2)

• Change in promoter methylation levels of ACE2

  Promoter methylation of ACE2 using pyrosequencing analysis with PyroMark Q24 (Qiagen, Germany).

  Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1]

• expression levels of miR-200c-3p in serum

  expression levels of miR-200c-3p in serum using qRT-PCR (ThermoFisher)

  Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1]

Secondary Outcomes (16)

• serum levels of Angiotensin II, ACE2 and Vitamin D

  Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1]

• Change in Modified Barthel Index (BI)

  Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1]

• Changes in the Montreal Cognitive Assessment (MoCA)

  Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1]

• Changes in the Cumulative Ilness Rating scale (CIRS)

  Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1]

• Change in Fugl-Meyer Assessment of Motor Recovery after Stroke for Upper Extremity portion (FMA-UL)

  Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1]

Study Arms (1)

Covid patients

Inpatients and outpatients admitted to the investigators' rehabilitation facility with covid symptoms

Device: Robotic assisted intervention; Genetic: epigenetic analyses; Diagnostic Test: biochemical analyses

Interventions

Robotic assisted intervention DEVICE

Conventional rehabilitation and Robotic treatment of the upper limb (30 sessions, 5 times a week) using a set of 4 robotic devices: Motore (Humanware); Amadeo, Diego, Pablo (Tyromotion). The training will include motor-cognitive exercises specifically selected to train spatial attention, vision and working memory, praxis, executive function, and speed of processing.

Covid patients

epigenetic analyses GENETIC

Epigenetic study: evaluation of methylation levels of ACE2 promoter and miR-200c-3p levels.

Covid patients

biochemical analyses DIAGNOSTIC_TEST

Biochemical analysis: the evaluation of serum levels of angiotensin II, ACE2 and Vitamin D.

Covid patients

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with first ischemic stroke (of ischemic or hemorrhagic aetiology) in subacute phase (within six months after the acute event), hospitalized at the participating intensive-extensive rehabilitation centers will be included

You may qualify if:

• stroke patients (hemorrhagic or ischemic) documented through Magnetic Resonance Imaging (MRI) or Computed Tomography (CT);
• NeuroCOVID19 stroke patients with double nasopharyngeal swab negative after 24 hours for SARS-Cov2.
• latency time within 6 months after stroke event;
• sufficient cognitive and language skills to understand the instructions related to the administration of the assessment scales and to sign informed consent;

You may not qualify if:

• behavioral and cognitive disorders that may interfere with the therapeutic activity;
• other orthopaedic or neurological complications that may interfere with the rehabilitation protocol;
• inability to understand and sign informed consent;

Sponsors & Collaborators

• Fondazione Don Carlo Gnocchi Onlus: lead

Study Sites (1)

Fondazione Don Carlo Gnocchi

Rome, 00168, Italy

Location

Related Publications (23)

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MeSH Terms

Conditions

Neurologic Manifestations; Stroke

Condition Hierarchy (Ancestors)

Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Study Officials

• Irene Aprile, MD,PHD

  IRCCS Fondazione Don Carlo Gnocchi

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Md, PhD, Principal Investigator, Head of Rehabilitation Unit

Study Record Dates

• First Submitted: February 22, 2021
• First Posted: February 23, 2021
• Study Start: September 4, 2020
• Primary Completion: December 16, 2022
• Study Completion: January 31, 2023
• Last Updated: July 18, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)