Gender Differences in Stroke With COVID-19: Epigenetic and Biochemical Study of ACE2 Receptor and Relationship With Rehabilitative Outcome
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 77
- 试验地点
- 1
- 主要终点
- expression levels of miR-200c-3p in serum
研究概览
简要总结
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
详细描述
A new coronavirus was identified in December 2019 in Wuhan, China as the causative agent of "Severe Acute Respiratory Syndrome" (SARS-CoV-2), a viral lung infection indicated by the acronym COVID-19 (coronavirus disease 2019). By the end of January 2020, this rapidly spreading virus had already infected more than 100,000 people in several countries, leading the World Health Organization to declare a "global emergency" [Wu et al 2020]. The clinical manifestations of COVID-19 can vary from the common cold to more serious lung diseases such as those observed in the "Severe Acute Respiratory Syndrome" (SARS) of 2002-2003 and the "Middle East Respiratory Syndrome" (MERS) of 2011.
The Sars-Cov2 virus, like other RNA viruses, also showed a form of neurovirulence with consequent involvement in some patients of the Central Nervous System (CNS) and Peripheral Nervous System (SNP) [Baig et al, 2020].
Neurological symptoms in patients with COVID-19 infection fall into three categories:
- neurological expressions of the symptoms of the underlying disease (headache, dizziness, dysfunction of consciousness, ataxia, epileptic manifestations and stroke)
- symptoms of neuro-peripheral origin (hypo-ageusia, hyposmia, neuralgia);
- symptoms of skeletal muscle damage, often associated with liver and kidney damage.
The first data on COVID-19 infection are in favor of neurological involvement in a variable percentage of cases with particular expression in more severe patients [Mao et al, 2020]. According to some authors, involvement of the nervous system may be partly responsible for respiratory impairment [Yan-Chao et al, 2020].
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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-Cov
- •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;
排除标准
- •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;
结局指标
主要结局
expression levels of miR-200c-3p in serum
时间窗: Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1]
expression levels of miR-200c-3p in serum using qRT-PCR (ThermoFisher)
Change in promoter methylation levels of ACE2
时间窗: Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1]
Promoter methylation of ACE2 using pyrosequencing analysis with PyroMark Q24 (Qiagen, Germany).
次要结局
- change in 10 Meter Walk Test (10MWT)([Time Frame: Baseline (T0), Treatment (6 weeks) (T1)])
- Change in Modified Barthel Index (BI)(Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1])
- change in Modified Ashworth Scale (MAS)([Time Frame: Baseline (T0), Treatment (6 weeks) (T1)])
- Change in Six-Minute Walking Test (6MWT)([Time Frame: Baseline (T0), Treatment (6 weeks) (T1)])
- Numerical Rating Scale (NRS)(Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1])
- change in Motricity Index (MI)([Time Frame: Baseline (T0), Treatment (6 weeks) (T1)])
- hand grip strenght test([Time Frame: Baseline (T0), Treatment (6 weeks) (T1)])
- pinch grip strenght test([Time Frame: Baseline (T0), Treatment (6 weeks) (T1)])
- Change in Time Up And Go (TUG)([Time Frame: Baseline (T0), Treatment (6 weeks) (T1)])
- Kinematic analysis([Time Frame: Baseline (T0), Treatment (6 weeks) (T1)])
- serum levels of Angiotensin II, ACE2 and Vitamin D(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])
- 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])
- Changes in the Cumulative Ilness Rating scale (CIRS)(Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1])
- Neuropathic Pain Four Questions (DN4)(Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1])
- Change in Functional Ambulation Classification (FAC)([Time Frame: Baseline (T0), Treatment (6 weeks) (T1)])
研究者
Irene Giovanna Aprile
Md, PhD, Principal Investigator, Head of Rehabilitation Unit
Fondazione Don Carlo Gnocchi Onlus