Cerebrovascular Changes in Multiple Sclerosis Patients
Cerebrovascular Changes in Multiple Sclerosis Patients
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).
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).
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.