Cerebrovascular Changes in Multiple Sclerosis Patients

July 24, 2020 updated by: safaa omeira ghaly said, Assiut University

Multiple sclerosis (MS) MS is a chronic disease containing the inflammatory, demyelinating, anddegenerative processes of the central nervous system. The inflammation, microglial activation, astrocyticgliosis, demyelination, and somewhat axonal loss inwhite matter and grey matter was present in the brainsof the patients with MS . Moreover, MS patientspresented a reduction in the cerebral blood flow (CBF)affecting both grey and white matter in positronemission tomography (PET) studies.

MS is the most common autoimmune disorder of the central nervous system. As of 2010, the number of people with MS was 2-2.5 million (approximately 30 per 100,000) globally, with rates varying widely in different regions. MS affects approximately 1000000 people between 17 and 65 years old world wide, the projected prevalence rate of MS for the white US population was 191 per 1000000 and the incidence rate was 7.3 per 1000000 persons .

the contribution of neurodegenerative processes in the disease pathogenesis has been increasingly recognized, especially with respect to possible mechanisms of progression. These may include axonal degeneration, mitochondrial injury, energy failure, hypoxia, oxidative damage, iron accumulation or global cerebral hypoperfusion . Interestingly, Cerebral vasomotor reactivity (CVMR) in MS may be impaired as well.

Although the cause of CVMR impairment in MS is not clear, several potential factors mightcontribute to this phenomenon.

For the purpose of clarity,we divide them into (1) vascular factors, (2) glial factors, and (3)neuronal factors:

  1. Vascular factor

    Blood-brain barrier (BBB) disruption might be anotherfactor contributing to CVMR impairment in neurodegenerative disorders. CVMR impairment could also be caused by an increase inthe concentration of vasoconstrictive agents. For instance,endothelin-1 (ET-1) - a potent vasoconstrictor, is overexpressed in the cerebral vessels of MS and elevated in both serumand cerebrospinal fluid of patients with MS.

  2. Glial factors

    Reactive astrocytes, i.e. hypertrophied astrocytes that overexpress GFAP (glial fibrillary acidic protein) have been described in virtually all CNS disorders including MS . they could also contribute to CVMR impairment through the production of ET-1 and possibly other vasoconstrictors Another way in which glial cells could contribute to the impairment of CVMR might be associated with their involvement in oxidative stress pathways. Glial pathology may also cause BBB dysfunction.

  3. Neuronal factors

It has been shown that cholinergic projections originating from the nucleus basalis induce cerebral vasodilation directly through the release of acetylcholine and indirectly through the stimulation of NO-releasing interneurons . there is evidence of a cholinergic deficit in MS.

From a clinical point of view, reduced white and gray matter CBF in patients with MS has thus far been associated with cognitive manifestations.

Cognitive impairment occurs in 40 to 65% of patients with MS and can have a considerable impact on occupational and social life. also reduced deep gray matter perfusion in MS negatively correlated with fatigue.

Cerebrovascular reactivity (CVR) is an inherent indicator of the dilatory capacity of cerebral arterioles for a vasomotor stimulus for maintaining a spontaneous and instant increase of CBF) in response to neural activation. The integrity of this mechanism is essential to preserving healthy neurovascular coupling. Transcranial Doppler ultrasound (TCD) is defined as a non-invasive ultrasound procedure to evaluate the changes in cerebral blood flow velocity (CBFV) . The high temporal resolution and non-invasive nature of TCD make it a useful tool in the assessment of integrative cerebrovascular function in terms of cerebral reactivity, autoregulation and neurovascular coupling (NVC).

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Unknown

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Multiple sclerosis (MS) MS is a chronic disease containing the inflammatory, demyelinating, anddegenerative processes of the central nervous system[FrischerJMet al, 2009]. The inflammation, microglial activation, astrocyticgliosis, demyelination, and somewhat axonal loss inwhite matter and grey matter was present in the brainsof the patients with MS [Wegner C et al, 2006]. Moreover, MS patientspresented a reduction in the cerebral blood flow (CBF)affecting both grey and white matter in positronemission tomography (PET) studies [Sun X et al, 1998].

MS is the most common autoimmune disorder of the central nervous system[Berer K et al,2014]. As of 2010, the number of people with MS was 2-2.5 million (approximately 30 per 100,000) globally, with rates varying widely in different regions. [Milo R et al ,2010] MS affects approximately 1000000 people between 17 and 65 years old world wide, the projected prevalence rate of MS for the white US population was 191 per 1000000 and the incidence rate was 7.3 per 1000000 persons [Mayr WTet al, 2003]. Another study of prevalence of Multiple Sclerosis in Egypt in age group >17years in a population number 21774 was about 13.74 per 100000 [El-Tallawy HNet al, 2013].

The contribution of neurodegenerative processes in the disease pathogenesis has been increasingly recognized, especially with respect to possible mechanisms of progression. These may include axonal degeneration, mitochondrial injury, energy failure, hypoxia, oxidative damage, iron accumulation or global cerebral hypoperfusion [Mahad DH et al, 2015, D'haeseleer M et al, 2015]. Interestingly, Cerebral vasomotor reactivity (CVMR) in MS may be impaired as well.

Although the cause of CVMR impairment in MS is not clear, several potential factors mightcontribute to this phenomenon.

For the purpose of clarity,we divide them into (1) vascular factors, (2) glial factors, and (3) neuronal factors:

  1. Vascular factor

    Blood-brain barrier (BBB) disruption might be anotherfactor contributing to CVMR impairment in neurodegenerative disorders [Alvarez JI, et al, 2013]. CVMR impairment could also be caused by an increase inthe concentration of vasoconstrictive agents. For instance,endothelin-1 (ET-1) - a potent vasoconstrictor, is overexpressed in the cerebral vessels of MS and elevated in both serumand cerebrospinal fluid of patients with MS [Haufschild T, et al,2001, D'haeseleer M, et al,2013].

  2. Glial factors

    Reactive astrocytes, i.e. hypertrophied astrocytes that overexpress GFAP (glial fibrillary acidic protein) have been described in virtually all CNS disorders including MS [Ben Haim L, et al, 2015]. they could also contribute to CVMR impairment through the production of ET-1 and possibly other vasoconstrictors Another way in which glial cells could contribute to the impairment of CVMR might be associated with their involvement in oxidative stress pathways [Haider L et al, 2011]. Glial pathology may also cause BBB dysfunction [Alvarez JI, et al, 2013].

  3. Neuronal factors

It has been shown that cholinergic projections originating from the nucleus basalis induce cerebral vasodilation directly through the release of acetylcholine and indirectly through the stimulation of NO-releasing interneurons [Hamel E. et al, 2006] there is evidence of a cholinergic deficit in MS [Kooi E-J, et al, 2011].

From a clinical point of view, reduced white and gray matter CBF in patients with MS has thus far been associated with cognitive manifestations [-Inglese M, et al, 2008, D'Haeseleer M et al, 2013].

Cognitive impairment occurs in 40 to 65% of patients with MS and can have a considerable impact on occupational and social life [Amato MP, et al, 2001]. also reduced deep gray matter perfusion in MS negatively correlated with fatigue [Vucic S, et al, 2010].

Cerebrovascular reactivity (CVR) is an inherent indicator of the dilatory capacity of cerebral arterioles for a vasomotor stimulus for maintaining a spontaneous and instant increase of CBF) in response to neural activation. The integrity of this mechanism is essential to preserving healthy neurovascular coupling. Transcranial Doppler ultrasound (TCD) is defined as a non-invasive ultrasound procedure to evaluate the changes in cerebral blood flow velocity (CBFV) [Powers J et al,2009]. The high temporal resolution and non-invasive nature of TCD make it a useful tool in the assessment of integrative cerebrovascular function in terms of cerebral reactivity, autoregulation and neurovascular coupling (NVC).

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
50

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

All patients are subjected to the following:

  1. History taking and full general and neurological examination.

  2. Laboratory tests:

    CBC-KFT-LFT-Na-K-PT-PC-INR..

  3. MRI brain and spinal cord:

    To confirm diagnosis of MS by experienced neuro-radiologist.

  4. Visual Evoked potential:

    Help to confirm diagnosis (detect central demyelination and disseminated in space), VEP was performed using the Nihon Kohden model). MEB-7102 (Nihon Kohden Corp., Tokyo, Japan).

  5. Expanded Disability Status Scale (EDSS) [Kurtzke JF. Et al, 1983]. This scale provides an overall rating of disabilities based on 0(normal neurological examination) to 10 (death due to MS) point scale, higher scores represent greater degree of disability.
  6. Transcranial doppler study

Description

Inclusion Criteria:

  1. Patients diagnosed with MS or diagnosis of CIS highly suggestive of MS according to revised McDonald's criteria 2010.
  2. MS patients aged (18-60 years) of both sexes.
  3. EDSS score (1-7).

Exclusion Criteria:

  1. History or current evidence of CNS diseases other than MS which may affect brain volume &cognition e.g. (Dementia prior to MS, parkinsonism, other inflammatory CNS diseases).
  2. History or current evidence of medical illness as endocrinal or metabolic which may affect cognitive function e.g. (hepatic, renal impairment or hypothyrodism).
  3. History or current intake of any drug that may affect cognitive function e.g (Antiepileptic, antipsychotic…).
  4. History or current evidence of depression (according to DSM -5- criteria &Hamilton depression scale) or any psychiatric disorder.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
1st group
30 patients were diagnosed with MS according to revised MacDonald's criteria 2017 & collected from Neuropsychiatry department in Assuit university hospital
Radiation: mri
mri brain & spinal cord
2nd group
30 healthy volunteers subjects matched with age, sex & education level were recruited from outpatient clinic neuropsychiatry department and included only if they had no current or previous history of any neurological illness and their neurological examination was free
Radiation: mri
mri brain & spinal cord

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
evaluate cerebrovascular changes in patients with MS byTCD, which is an easy applicable and non-invasivebedside technique
Time Frame: 1 year
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Assiut University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 1, 2020

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 1, 2020

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 15, 2018

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 16, 2018

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 17, 2018

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 27, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 24, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • CVSIMSP

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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