Background: Axonal degeneration is related to long-term disability in patients with multiple sclerosis (MS). The underlying mechanism remains ill understood but appears to involve axonal energetic dysfunction. A globally impaired cerebral blood flow (CBF) has been observed in the normal-appearing white matter (NAWM) of patients with MS, which is probably related to astrocytic overexpression of endothelin-1 (ET-1). Cerebral hypoperfusion has been associated with reduced mitochondrial activity and disabling symptoms (e.g. fatigue and cognitive decline) of MS. Countering this process could therefore be beneficial in the disease course. Short-term CBF restoration with a single 62.5-mg dose of the ET-1 receptor antagonist bosentan has already been demonstrated in patients with MS. Methods: The ROCHIMS study is a proof-of-concept double-blind randomized clinical trial in which patients with relapsing-remitting MS will receive either 62.5 mg bosentan or matching placebo twice daily during 28 ± 2 days. Clinical evaluation and brain magnetic resonance imaging (MRI) will be performed at baseline and treatment termination. Based on previous work, we expect a global increase of CBF in the individuals treated with bosentan. The primary outcome measure is the change of N-acetyl aspartate in centrum semiovale NAWM, which is a marker of regional axonal mitochondrial activity. Other parameters of interest include changes in fatigue, cognition, motor function, depression, and brain volume.
It has been reported that nesting is important for heat conservation, reproduction and shelter and shown to relate to brain lesions, pharmacological agents and genetic mutations. 33 We found that BCAS caused impaired nesting ability, and it was attenuated by EE, which is a new finding in the BCAS mouse model. BCAS plus limited exposure to EE mice tended to make better nests compared to other BCAS subgroups. These results suggest that EE after chronic cerebral hypoperfusion could protect changes in different cognitive domains or could attenuate mild undetectable sensory-motor deficit involved in nesting ability.
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Abstract: Chronic cerebral hypoperfusion (CCH) is a basic pathological process that is comorbid with brain diseases, such as vascular Parkinsonism and Alzheimer’s disease. Icariside II (ICS II), which is one of the main metabo- lites of icariin, has anti-inflammatory and antioxidant effects and protects against ischemic brain injury. This study aims to investigate the neuroprotective effects of ICS II on neuronal axon regeneration-related factors in a CCH rat model. Sprague-Dawley (SD) rats were divided into the following four groups: sham group, model group and 4 and 8 mg/kg/day ICS II administration groups. Learning and spatial memory functions were tested using a Morris water maze. Pathological changes were observed in the rat hippocampal tissue by hematoxylin and eosin (H&E) staining. Neuronal axon regeneration-related proteins (GAP-43, MAP-2 and Nogo-A) were observed by immunohistochemical staining and detected by the average optical density method. The results showed that 8 mg/kg/day of ICS II can effectively reduce the escape latency and prolong the target quadrant residence time at 12 weeks and that ICS II can improve the histopathological changes in the CA1 area of the rat hippocampus. Moreover, ICS II administration at 8 mg/kg/day significantly increased GAP-43 and MAP-2 expression and reduced Nogo-A expression in the CA1 area of the rat hippocampus at 12 weeks; however, significant differences were not observed at 4 and 8 weeks. Hence, ICS II at a dosage of 8 mg/kg/day could promote learning and memory abilities and improve histopathologi- cal changes in the rat hippocampus in a CCH rat model. These results may be related to the promotion of neuronal axon regeneration in the CA1 area of the hippocampus under increases in hippocampal GAP-43 and MAP-2 protein expression and decreased Nogo-A protein expression.
Upon activation, microglia undergo fundamental mor- phological changes in response to different environmen- tal stimuli. Microglial activation results in hypertrophy, with thicker and less radially projecting processes  and expresses mitochondrial translocator protein (TSPO) . The response of microglia might be dependent on different degrees of activation and may be detrimental . Tumour necrosis factor-alpha (TNF-α) produced by activated microglia plays a critical role in the induc- tion of neuronal death in Alzheimer’s disease . In addition, increased proliferation of microglia was evident in human AD cases with increased colony-stimulating factor 1 receptor (CSF1R) expression, and inhibition of CSF1R attenuated microglial proliferation in a mice model of AD . Previous studies have suggested that chronic over-activation of microglia results in the over- production of cytotoxic factors such as proteases (i.e. matrix metalloproteinase-2 (MMP-2)), reactive oxygen species and pro-inflammatory cytokines [63 – 65] that promote neurotoxicity and neuronal damage. Chronic cerebral hypoperfusion induces MMP-2 in microglia . MMP-2 plays a critical role in the BBB disruption, glial activation, and WM lesions after chronic cerebral hypoperfusion . In our study, BCAS-std and BCAS- full demonstrated a greater rate of microglial over- activation, which corresponds to more CC atrophy. Thus, WM damage observed in BCAS mice may occur due to microglial activation-induced neuronal/axonal damage. Identifying molecular targets  of microglial activation and microglial suppressant agents such as
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A substantial amount of evidence indicates that chronic cerebral hypoperfusion (CCH), a state of chronic cere- bral blood flow reduction, is associated with several cerebrovascular and neurodegenerative disorders in- cluding Alzheimer’s disease (AD), carotid stenosis/oc- clusion, cerebral arteriovenous malformation, dural arteriovenous fistula, moyamoya disease and cerebral small vessel disease [1–6]. In our previous study [7– 11], we found that CCH may contribute to neuronal apoptosis, cognitive impairment, chronic neuroinflam- matory responses and abnormal excessive autophagy in the frontal cortex and hippocampus of rats, resulting in cerebral ischemic damage. The fatty acid amide hydro- lase inhibitor URB597 (URB) could be a candidate for alleviating chronic intracranial ischemic injury, as it could offer increased selective protection with less risk of the undesirable side effects that have been observed with cannabinoid receptor agonists capable of activat- ing all accessible receptors indiscriminately [7–11]. Thus, we believe that URB might be a promising thera- peutic agent for the treatment and management of CCH. However, the mechanisms underlying URB treat- ment are complex, and require further clarification.
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perfused mice. The presence of Thioflavin S positive Aβ deposits within astrocyte endfeet confirms the passage of Aβ from the blood into the perivascular space, where they aggregate due a faulty clearance. Six weeks later, Aβ vascu- lar deposits were seeded in brain parenchyma as small Aβ Congo Red positive aggregates, which were detected by intravital microscopy in the brain of living mice. Interest- ingly, brain reperfusion or the administration of high dose of glucose prevented Aβ deposition in ipsilateral brain capillaries. Taken together these data indicate that mild chronic cerebral hypoperfusion directly contributes in the initiation of Aβ deposition and aggregation cascades. Our study supports recent data showing that cerebral hypoper- fusion accelerates cerebral amyloid angiopathy (CAA) pathology in humans and CAA mice model, by deeply af- fecting CBF and neurovascular function .
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Neuroinflammation has been known to be correlated with the occurrence of white matter lesions induced by chronic cerebral hypoperfusion . The inflammatory re- sponse leads to activation of resident glial cells, such as microglia and astrocytes, and upregulation of inflamma- tory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), aggravates the inflammation after chronic cerebral hypoperfusion . Fructus mume ( F. mume ), the processed unripe fruit of Prunus mume, has been utilized for the treatment of gastrointestinal dis- eases in Asian countries for thousands of years. Several re- ports have demonstrated that F. mume is useful for the treatment of colitis in an inflammatory bowel disease model  and attenuates lipopolysaccharide-induced in- flammation in RAW 264.7 cells by inhibiting the produc- tion of nitric oxide, prostaglandin E2, cyclooxygenase-2 (COX-2), and interleukin-6 (IL-6) . However, the pro- tective effect and mechanism of action of F. mume have not yet been fully investigated in various pathological con- ditions. Therefore, the aim of this study was to evaluate the effect of F. mume on the white matter and hippocam- pal damage in chronic cerebral hypoperfused rat and the potential efficacy of F. mume for the treatment of cogni- tive impairment.
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myelin sheath, a key element of white matter . De- myelination induced by chronic cerebral hypoperfusion can damage not only white matter but also gray matter including the hippocampus [48, 49]. Specifically, it has been hypothesized that proinflammatory molecules re- leased by microglia accelerate myelin degradation [24, 50]. Confirming previous reports , the expression of MBP was down-regulated in response to chronic BCCAo in the hippocampus and white matter. However, the decrease in MBP was not observed in rats with chronic BCCAo given SM extract. These findings suggest that SM may suppress the breakdown of MBP following chronic cerebral hypo- perfusion. In addition, these data imply that SM might be beneficial in the treatment of other demyelinating diseases including multiple sclerosis . Further studies are needed to determine the mechanisms underlying the ef- fects of SM on myelin disruption.
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Because of the lack of reliable clinical data, the effect of volume therapy (HES 130/0.4) on cerebral hypoper- fusion due to severe ICA/MCA stenosis or occlusion is largely unsettled. In this trial, three types of patients with cerebral hypoperfusion will be recruited: non-acute ischemic stroke, TIA and asymptomatic patients. Al- though volume therapy could possibly decrease blood viscosity and may increase cerebral perfusion or oxygen delivery, previous studies [13,24,28] focused on acute is- chemic stroke with treatment windows from 6 hours to 48 hours resulted no improvement in outcome or sur- vival at the endpoints. In this trial, we’d like to enroll patients with non-acute ischemic stroke (time of stroke onset: 72 hours to 3 weeks) for the following reasons: 1. variable cerebral hypoperfusion state and higher risk of hemorrhagic transformation may appear in patients with acute ischemic stroke (< 72hours); 2. from 72 hours to 3 weeks of stroke onset, patients’ emotional state and cerebral auto-regulation are relatively stable. Cerebral hypoperfusion with severe intracranial atherosclerosis is one of common causes of ischemic stroke and TIA. Un- less the collateral blood supply is sufficient to prevent is- chemia, multiple remote spot-like infarctions may occur within the hypoperfused brain territory. Certainly, the superiority of surgical interventions over medical ther- apy has been confirmed in symptomatic patients with severe ICA stenosis [8,29]. However, for the asymptom- atic patients with severe or moderate ICA stenosis, the role of surgical interventions remains uncertain. For the
Decreased cerebral blood supply, which is associated with dementia, results in chronic cerebral hypoperfusion (CCH), a physiopathological mechanism of neural dysfunction in Alzheimer’s disease. Eurycoma longifolia (EL) Jack has been documented to have multiple biological activities. The current study aimed to determine the potential effect of EL root extracts in CCH using a 2-vessel occlusion (2VO) model. CCH was induced by a permanent bilateral ligation of the common carotid arteries in male Sprague–Dawley rats. The experimental groups were divided as follows: a sham-operated group, a 2VO group without any treatment, and a 2VO group that was orally administered EL extract (100 mg/kg/day) for 3 days before the day of 2VO surgery and continued until the end of postoperative week 8. Spatial memory performance was assessed by the Morris water maze test. Moreover, malondialdehyde (MDA) concentration and superoxide dismutase activity, glutathione level, and C-reactive protein (CRP) concentration in serum were measured. CCH rats showed significant cognitive impairment, decreased antioxidant activities, and increased MDA and CRP concentration in serum. The group that was orally administered EL extract showed a slight preservation of cognitive function, enhanced antioxidant activity, decreased MDA and CRP concentration than did the untreated 2VO group. EL offers potential neuroprotective effects due to its antioxidant and anti-inflammatory properties.
Background: Post-stroke dementia (PSD) is one of the major consequences after stroke. Chronic cerebral hypoperfusion (CCH) can induce vascular cognitive impairment and potentiate amyloid pathology. We investigated how CCH contributes to the development of PSD after stroke in the context of neuroinflammation and amyloid pathology. Methods: We designed a unique animal model for PSD. We performed middle cerebral artery occlusion (MCAO) surgery in rats mimicking acute territorial infarct, which was followed by bilateral common carotid artery occlusion (BCCAo) surgery mimicking CCH. We performed behavioral tests including neurologic function test and water maze task and histological investigations including neuroinflammation, neuronal cell death, amyloid pathology, and aquaporin 4 (AQP4) distribution.
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The model of ageing rats with cerebral hypoperfusion was established by per- manent occlusion of bilateral common carotid arteries (2VO). In brief, after in- duction of anesthesia with chloral hydrate (350 mg/kg, intraperitoneal (i.p.)), both common carotid arteries were exposed through a midline ventral incision and permanently ligated with silk suture. The surgical wound was then sutured. After operation, alive rats were randomly divided into 2VO group (1.7, 14, 21 and 28 days after operation). The sham-operation group underwent an identical procedure without ligation of the bilateral common carotid arteries.
Eight weeks after BCCAO or sham surgery, rats under- went MWM test to assess spatial learning and memory. There was no significant difference in escape latency on the first day among the four groups. Either DM or CCH alone slightly prolonged escape latency compared with the sham group. However, DM combined with CCH could significantly prolong escape latency relative to DM and CCH group, especially on days 4–5. But there was no significant difference in the DM group and CCH group in the whole test (Fig. 2a). In the probe trial, both the DM group and the CCH group performed poorer than the sham group, with fewer crossings over the ori- ginal platform and less time spent in the target quadrant. Meanwhile, significant deterioration was observed in the DM CCH group compared with DM and CCH group (Fig. 1b, c). There was no difference among the experi- mental groups with respect to swimming speed (Fig. 1d). Thus, diabetes is synergistic with hypoperfusion to in- duce significant learning and memory impairment in our rat model.
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As an age-related neurodegenerative disease, large- scale epidemiological studies have identified multiple vascular risk factors in AD patients, which contribute to the onset of the disease [28, 29]. Thus, controlling these vascular risk factors may prevent AD [30, 31]. Global and focal cerebral hypoperfusion are reported in AD, indicating the presence of brain tissue hypoperfu- sion [3–5]. Longitudinal studies have demonstrated that decreased cerebral perfusion in MCI could predict pro- gression to AD . In comparison to CN controls of similar ages, postmortem microscopic pathologic stud- ies showed significant structural changes of the cerebral vasculature in AD, such as increased prevalence of microinfarcts, loose capillary density, capillary kinking, looping, and twisting . These changes in the vessel systems may explain the impaired microcirculation, resulting in insufficient tissue perfusion. Image markers of large vessels measured with modalities such as MRI or TCD are helpful but mostly non-specific for asses- sing cerebral microvascular dysfunction. A non-invasive and inexpensive way to assess vascular alteration in the eye at a microvascular level, as performed in the present study, may also offer early diagnosis and subse- quent monitoring of cerebral disease progression and efficacy of therapy.
The normal echocardiography, vessel imaging, spinal ﬂuid, rheumatology laboratories, blood cultures, and absence of fever argue against cardioembolism, endocarditis, arterial dissection, RCVS, vasculitis, and infection. There was no history of hypotension, hypoxia, arrhythmia, or cardiac arrest. Moreover, the patient’s mean arterial pressure was normal throughout her hospital stay, making cerebral hypoperfusion unlikely. The infarct distribution, in combination with en- cephalopathy, peripheral eosinophilia, and cardiac injury, suggest stroke secondary to hypereosinophilic syndrome.
Children with cerebral palsy are more difficult to participate in games, daily activities and social interactions, so that they are more dependent on their parents [40, 41]. Parenting practice makes a significant contribution to children’s developmental outcomes. Positive parent-child interaction contributes to the development of children with cerebral palsy. Regardless of the degree of disability of the child, the parent-child relationship is closely related to parents’ pain, instructions and inter- action time. Therefore, it is important to con- cern parental mental health problems in early childhood intervention. Furthermore, it is nec- essary to in-depth explore how therapists sup- port parents to implement therapeutic strate- gies to minimize negative influence on the developing parent-child relationship [42, 43]. Conclusion
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MATERIALS AND METHODS: One hundred six migraineurs who underwent MR imaging, including DSC perfusion, were included in the study. In patients with apparent perfusion asymmetry, we used ROI analysis encompassing 18 infra- and supratentorial ROIs to account for differences in regional cerebral blood ﬂow and volume. The presence of cerebellar hypoperfusion was calculated using an asymmetry index, with values of ⬎ 10% being considered signiﬁcant.
At the start of the experiment, the subject was told to sit comfortably on a chair. Heart rate, systolic and diastolic blood pressure of each subject was monitored using an automatic blood pressure monitor device (HEM-907, Omron Healthcare, Hoofddorp, The Netherlands) prior to the acquisition of PPG signals. A sphygmomanometer blood pressure cuff was then wrapped around the brachial artery of the right arm. The index finger of the same arm was placed in the custom made multimode PPG probe. PPG recording commenced prior to any occlusion. Artificial hypoperfusion was then induced by gradually occluding the brachial artery using the sphygmo- manometer. The pressure was exerted with increments of 15 mmHg and PPG signals recorded from all three modes for a period of 30 seconds. Once the previously recorded systolic pressure was reached, the pressure in the sphygmomanometer cuff was released and PPGs recorded for a further 30 seconds. Peak detection algorithm was used to determine the ac PPG amplitudes. The mean of the PPG amplitudes recorded for each 30 second epoch for each occluding pressure for both wavelengths were then calculated. Paired Student’s t-tests were used to determine whether there were statistically significant differences in amplitude between different modes for all occlusion pressures. A value of p <= 0.05 was considered statistically significant.
Apoptosis was induced in tissue that experienced severe perfusion deficits and resulted in severe injury scores, rather than in penumbra, a moderately hypoperfused tissue periph- eral to the ischemic core. Although different definitions of penumbra were given based on various functional and meta- bolic parameters (13), the two common features of penumbra include partial disruption of cerebral blood flow and reversibil- ity of the ischemic injury. As a tissue at ‘risk,’ such areas are thought to be potentially resuscitatable and are the targets for therapeutic intervention. Our data demonstrate that moderate reductions of cerebral perfusion alone did not lead to a signifi- cant induction of apoptosis in cat brain during the duration of reperfusion that we studied. However, selective cell popula- tions may be preferentially vulnerable to more subtle reduc- tions of cerebral microcirculation that otherwise do not disturb metabolic and functional integrity. It may be that there is an “ischemic threshold” of hypoperfusion that activates apopto- sis. Recent data have demonstrated that at later time points af- ter mild transient cerebral ischemia in the rat, a substantial number of neurons from the periinfarct area undergo apopto- sis (36, 37), and that more severe ischemic insult resulted in a higher number of apoptotic neurons. Species differences may in part account for differences between the observations re- ported here and previously published data (10). The rat is a species known to have lower brain collateral blood supply and less extended penumbra areas (13) than is found in cats.
As noted above, most scholars believe that the interruption of the CPC pathway may be the mechanism of CCD occurrence. Nguyen et al. considered that the severity of CCD is relevant with the degree of influence on the CPC path- way of primary lesions . Studies have shown that the CPC pathway is the most important nerve fiber pathway between the cerebral cor- tex and contralateral cerebellar hemisphere, which consists of pons fibres from the cortex focused inward the forelimb and hindlimb of the internal capsule to ipsilateral pons, as well as fibers from pons to the contralateral cerebellum. When neuronal axonal rupture or injury caused by various brain damage occur, Wallerian degeneration may appear in proximal axons of the damage zone and distal axons of the damage zone may gradually undergo de- generation and disintegration from close to far, resulting in pathway interruption. Hence, corti- cal excitatory impulses cannot be transmitted to the contralateral cerebellum. When nerve impulses transmitted into the contralateral cer- ebellum from the supratentorial brain tissue decline, CCD occurs and functional inhibition appears . Therefore, the occurrence and development of CCD after cerebral infarction may be related to age, lesion area and location of the cerebral infarction, as well as paralysis, muscle strength and so on. All of those will be described in detail in the following.
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