The Bilateral Carotid Artery Stenosis (BCAS) Model of Vascular Dementia.

Vascular dementia is the second most common form of dementia after Alzheimer's disease. Chronic cerebral hypoperfusion is a key contributor to the development of vascular dementia. In this chapter, we describe the surgical procedures used for bilateral carotid artery stenosis (BCAS) surgery to induce chronic cerebral hypoperfusion. Mice that undergo BCAS surgery develop the hallmarks of vascular dementia including white matter lesions, neuroinflammation, and cognitive impairment. This technique may be used for studies of chronic cerebral hypoperfusion and vascular dementia in mice.

Clinical effect of carotid stenting on cognitive abilities - possible evaluation using candidates for biomarkers.

Micro- and macrovascular consequences of atherosclerosis, arterial hypertension, dyslipidemia, and smoking can affect neurotransmission and markers for neuronal activity. The potential direction and specifics are under study. It is also known that optimal control of hypertension, diabetes, and dyslipidemia in midlife may positively affect cognitive functioning later in life. However, the role of hemodynamically significant carotid stenoses in neuronal activity markers and cognitive functioning is still being debated. With the increased use of interventional treatment for extracranial carotid disease, the question of whether it might affect neuronal activity indicators and whether we can stop or even reverse the path of cognitive deterioration in patients with hemodynamically severe carotid stenoses naturally emerges. The existing state of knowledge provides us with ambiguous answers. We sought the literature for possible markers of neuronal activity that can explain any potential difference in cognitive outcomes and guide us in the assessment of patients throughout carotid stenting. The combination of biochemical markers for neuronal activity with neuropsychological assessment and neuroimaging may be important from practical point of view and may provide the answer to the question for the consequences of carotid stenting for long-term cognitive prognosis.

[Study of the effect of Unifuzol on cognitive impairment and damage to the hippocampus and cerebral cortex during course administration to rats with bilateral stenosis of the common carotid arteries, causing chronic circulatory failure]. / Vliyanie preparata Unifuzol na sostoyanie kognitivnykh funktsii v usloviyakh eksperimental'nogo khronicheskogo narusheniya mozgovogo krovoobrashcheniya.

OBJECTIVE: To study the effect of Unifuzol (L-arginine sodium succinate) on cognitive impairment, cerebral blood flow, and damage to the tissues of the hippocampus and cerebral cortex during a 10-day course of administration to rats with chronic cerebral ischemia (CCI) caused by bilateral stenosis of the common carotid arteries (CCA). MATERIAL AND METHODS: The study was conducted on male rats with CCI caused by bilateral stenosis of the CCA by 60%. 40 days after surgery, rats received Unifusol (21, 42 and 84 ml/kg), nicergoline (10 mg/kg), citicoline (500 mg/kg) or placebo (0.9% NaCl) for 10 days. Next, cognitive impairments were assessed in the Morris Water Maze and the New Object Recognition (NOR) test, as well as the level of motor and exploratory activity in the Open Field test. The level of cerebral blood flow was determined immediately after the CCA stenosis and at the end of the experiment. Animals were euthanized in a CO2 incubator, after which the brain was removed and subjected to morphometric analysis. RESULTS: In animals that were modeled with CCA stenosis, pronounced behavioral and cognitive impairments occurred as a result of a decrease in blood flow in the vessels of the brain and subsequent changes in the tissues of the hippocampus and the cerebral cortex. Intravenous course administration of Unifuzol at doses of 42 and 84 ml/kg to animals with CCI was comparable in efficiency to nicergoline and citicoline, which was expressed in greater preservation of the cognitive abilities of animals in the Morris Water Maze and NOR tests. In the Open Field test, animals injected with Unifusol at doses of 42 and 84 ml/kg performed more acts of motor and exploratory activity than animals from the placebo group, and had a higher level of cerebral blood flow (compared to animals that were injected with citicoline). Based on the results of a morphological study, it was found that the most significant neuroprotective effect was provided by nicergoline and Unifuzol (at doses of 42 and 84 ml/kg). CONCLUSION: Unifuzol at a course of administration at doses of 42 and 84 ml/kg, comparable to the reference drugs nicergoline and citicoline, reduces the severity of psychoneurological deficit in animals with CCI, comparable to them improves the microcirculation of brain tissues, preventing damage to brain tissues.

Bilateral Carotid Artery Stenosis and Cerebral Blood Flow Outcomes.

Bilateral carotid artery stenosis (BCAS) is a valid approach for modeling vascular dementia (VaD) in mice as it induces cerebral hypoperfusion and produces white matter degeneration and cognitive impairment. VaD is one of the major causes of cognitive impairment and currently has no approved therapy; hence its preclinical modeling is warranted for investigating potential therapeutic compounds. BCAS enables the characterization of brain pathology and associated cognitive phenotype of VaD. In this chapter, we describe the surgical method of inducing BCAS in mice, using titanium micro-coils, and we report cerebral blood flow changes before and after surgical induction as well as some histological findings in the corpus callosum of diabetic mice subjected to long-term BCAS.

Carotid disease, cognition, and aging: time to redefine asymptomatic disease?

There is an increasing appreciation of the vascular contributions in the development of age-related cognitive impairment and dementia1,2. Identifying risk and maintaining cognitive health for successful aging is ever relevant in our aging population. Carotid disease, a well-established risk factor for stroke and often a harbinger of other vascular disease states, is also emerging as another vascular risk factor for age-related cognitive decline. When combined with vascular risk factors, the incidence of age-related carotid disease can be as high as 70%3,4. Historically, carotid disease has been dichotomized into two large groups in trial design, outcome measurements, and treatment decisions: symptomatic and asymptomatic carotid artery stenosis. The dichotomous distinction between asymptomatic and symptomatic carotid stenosis based on existing definitions may be limiting the care we are able to provide for patients classified as "asymptomatic" from their carotid disease. Medically, we now know that these patients should be treated with the same intensive medical therapy as those with "symptomatic" carotid disease. Emerging data also shows that hypoperfusion from asymptomatic disease may lead to significant cognitive impairment in the aging population, and it is plausible that most "age-related" cognitive changes may be reflective of vascular impairment and neurovascular dysfunction. While over the past 30 years medical, surgical, and radiological advances have pushed the field of neurovascular disease to significantly reduce the number of ischemic strokes, we are far from any meaningful interventions to prevent vascular cognitive impairment. In addition to including cognitive outcome measures, future studies of carotid disease will also benefit from including advanced neuroimaging modalities not currently utilized in standard clinical imaging protocols, such as perfusion imaging and/or functional connectivity mapping, which may provide novel data to better assess for hypoxic-ischemic changes and neurovascular dysfunction across diffuse cognitive networks. While current recommendations advise against widespread population screening for asymptomatic carotid stenosis, emerging evidence linking carotid stenosis to cognitive impairment prompts us to re-consider our approach for older patients with vascular risk factors who are at risk for cognitive decline.

Neurogranin as an important regulator in swimming training to improve the spatial memory dysfunction of mice with chronic cerebral hypoperfusion.

BACKGROUND: Vascular cognitive impairment caused by chronic cerebral hypoperfusion (CCH) has become a hot issue worldwide. Aerobic exercise positively contributes to the preservation or restoration of cognitive abilities; however, the specific mechanism has remained inconclusive. And recent studies found that neurogranin (Ng) is a potential biomarker for cognitive impairment. This study aims to investigate the underlying role of Ng in swimming training to improve cognitive impairment. METHODS: To test this hypothesis, the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) system was utilized to construct a strain of Ng conditional knockout (Ng cKO) mice, and bilateral common carotid artery stenosis (BCAS) surgery was performed to prepare the model. In Experiment 1, 2-month-old male and female transgenic mice were divided into a control group (wild-type littermate, n = 9) and a Ng cKO group (n = 9). Then, 2-month-old male and female C57BL/6 mice were divided into a sham group (C57BL/6, n = 12) and a BCAS group (n = 12). In Experiment 2, 2-month-old male and female mice were divided into a sham group (wild-type littermate, n = 12), BCAS group (n = 12), swim group (n = 12), BCAS + Ng cKO group (n = 12), and swim + Ng cKO group (n = 12). Then, 7 days after BCAS, mice were given swimming training for 5 weeks (1 week for adaptation and 4 weeks for training, 5 days a week, 60 min a day). After intervention, laser speckle was used to detect cerebral blood perfusion in the mice, and the T maze and Morris water maze were adopted to test their spatial memory. Furthermore, electrophysiology and Western blotting were conducted to record long-term potential and observe the expressions of Ca2+ pathway-related proteins, respectively. Immunohistochemistry was applied to analyze the expression of relevant markers in neuronal damage, inflammation, and white matter injury. RESULTS: The figures showed that spatial memory impairment was detected in Ng cKO mice, and a sharp decline of cerebral blood flow and an impairment of progressive spatial memory were observed in BCAS mice. Regular swimming training improved the spatial memory impairment of BCAS mice. This was achieved by preventing long-term potential damage and reversing the decline of Ca2+ signal transduction pathway-related proteins. At the same time, the results suggested that swimming also led to improvements in neuronal death, inflammation, and white matter injury induced by CCH. Further study adopted the use of Ng cKO transgenic mice, and the results indicated that the positive effects of swimming training on cognitive impairments, synaptic plasticity, and related pathological changes caused by CCH could be abolished by the knockout of Ng. CONCLUSION: Swimming training can mediate the expression of Ng to enhance hippocampal synaptic plasticity and improve related pathological changes induced by CCH, thereby ameliorating the spatial memory impairment of vascular cognitive impairment.

Editor's Choice - Effect of Carotid Interventions on Cognitive Function in Patients With Asymptomatic Carotid Stenosis: A Systematic Review.

OBJECTIVE: To determine the effect of carotid endarterectomy (CEA) and carotid artery stenting (CAS) on early (baseline vs. maximum three months) and late (baseline vs. at least five months) cognitive function in patients with exclusively asymptomatic carotid stenoses (ACS). METHOD: Searches were conducted in PubMed/Medline, Embase, Scopus, and the Cochrane library. This systematic review includes 31 non-randomised studies. RESULTS: Early post-operative period: In 24 CEA/CAS/CEA+CAS cohorts (n = 2 059), two cohorts (representing 91/2 059, 4.4% of the overall study population) reported significant improvement in cognitive function, while one (28/2 059, 1%) reported significant decline. Three cohorts (250/2 059, 12.5% reported "mixed findings" where some cognitive scores significantly improved, and a similar proportion declined. The majority (nine cohorts; 1 086/2 059, 53%) reported no change. Seven cohorts (250/2 059, 12.1%) were mostly unchanged but one to two individual test scores improved, while two cohorts (347/2 059, 16.8%) were mostly unchanged with one to two individual test scores worse. Late post-operative period: In 21 cohorts (n = 1 554), one (28/1 554, 1.8%) reported significantly worse cognitive function, one reported significant improvement (24/1 554, 1.5%), while a third (19/1 554, 1.2%) reported "mixed findings". The majority were unchanged (six cohorts; 1 073/1 554, 69%) or mostly unchanged, but with one to two cognitive tests showing significant improvement (11 cohorts; 386/1 554, 24.8%). Overall, there was a similar distribution of findings in small, medium, and large studies, in studies with controls vs. no controls, in studies comparing CEA vs. CAS, and in studies with shorter/longer late follow up. CONCLUSION: Notwithstanding accepted limitations regarding heterogeneity within non-randomised studies, CEA/CAS rarely improved overall late cognitive function in ACS patients (< 2%) and the risk of significant cognitive decline was equally low (< 2%). In the long term, the majority were either unchanged (69%) or mostly unchanged with one to two test scores improved (24.8%). Until new research identifies vulnerable ACS subgroups (e.g., impaired cerebral vascular reserve) or provides evidence that silent embolisation from ACS causes cognitive impairment, evidence supporting intervention in ACS patients to prevent/reverse cognitive decline is lacking.

Treatment with edaravone improves the structure and functional changes in the hippocampus after chronic cerebral hypoperfusion in rat.

This study aimed to find out cellular and electrophysiological effects of the edaravone (EDR) administration following induction of vascular dementia (VaD) via bilateral-carotid vessel occlusion (2VO). The rats were randomly divided into control, sham, 2VO + V (vehicle), and 2VO + EDR groups. EDR was administered once a day from day 0-28 after surgery. The passive-avoidance, Morris water-maze, and open-field tests were used for evaluation of memory, locomotor, and anxiety. The field-potential recording was used for assessment of electrophysiological properties of the hippocampus; and after sacrificing, the cerebral hemispheres were removed for stereological study and evaluation of MDA levels. The long-term potentiation (LTP), paired-pulse ratio (PPR), and input-output (I/O) curves were evaluated as indexes for long-term and short-term synaptic plasticity, and basal-synaptic transmission (BST), respectively. The 2VO led to increases in MDA level with considerable neuronal loss and decreases in the volume of the hippocampus, along with a reduction in the BST and LTP induction which was associated with a decrement in PPR and ultimate loss in memory with higher anxiety behavior. However, administration of EDR caused a decline in MDA and prevented the neural loss and volume of the hippocampus, rescued BST and LTP depression, improved memory and anxiety without any effects on PPR. Therefore, most likely through the improvement of MDA level, and the hippocampal cell number and volume, EDR leads to recovery of synaptic plasticity and behavioral performance. Because of the LTP rescue, without recovery of PPR, it is likely that the EDR improved LTP through the post-synaptic neurons.

Editor's Choice - Asymptomatic Carotid Stenosis and Cognitive Impairment: A Systematic Review.

OBJECTIVE: The aim was to evaluate the relationship between asymptomatic carotid stenosis (ACS) of any severity and cognitive impairment and to determine whether there is evidence supporting an aetiological role for ACS in the pathophysiology of cognitive impairment. DATA SOURCES: PubMed/Medline, Embase, Scopus, and the Cochrane library. REVIEW METHODS: This was a systematic review (35 cross sectional or longitudinal studies) RESULTS: Study heterogeneity confounded data interpretation, largely because of no standardisation regarding cognitive testing. In the 30 cross sectional and six longitudinal studies (one included both), 33/35 (94%) reported an association between any degree of ACS and one or more tests of impaired cognitive function (20 reported one to three tests with poorer cognition; 11 reported four to six tests with poorer cognition, while three studies reported seven or more tests with poorer cognition). There was no evidence that ACS caused cognitive impairment via silent cortical infarction, or via involvement in the pathophysiology of lacunar infarction or white matter hyperintensities. However, nine of 10 studies evaluating cerebral vascular reserve (CVR) reported that ACS patients with impaired CVR were significantly more likely to have cognitive impairment and that impaired CVR was associated with worsening cognition over time. Patients with severe ACS but normal CVR had cognitive scores similar to controls. CONCLUSION: Notwithstanding significant heterogeneity within the constituent studies, which compromised overall interpretation, 94% of studies reported an association between ACS and one or more tests of cognitive impairment. However, "significant association" does not automatically imply an aetiological relationship. At present, there is no clear evidence that ACS causes cognitive impairment via silent cortical infarction (but very few studies have addressed this question) and no evidence of ACS involvement in the pathophysiology of white matter hyperintensities or lacunar infarction. There is, however, better evidence that patients with severe ACS and impaired CVR are more likely to have cognitive impairment and to suffer further cognitive decline with time.

Evaluation of Neurocognitive Abilities in Patients Undergoing Carotid Endarterectomy Surgery.

OBJECTIVE: To evaluate the differences in neurocognitive abilities between the preoperative and postoperative periods following carotid endarterectomy (CEA), due to carotid artery stenosis, and to evaluate the effectiveness of CEA on neurocognitive abilities in the future. MATERIAL AND METHODS: Thirty-eight cases of CEA surgery at Bozok University Faculty of Medicine Research Hospital between January 2015 and June 2020 were examined. Neurocognitive tests were performed on carotid endarterectomy patients one day before the operation and on the 2nd, 4th, and 30th postoperative days. The effect of CEA on cognitive results has been investigated. RESULTS: Of the patients, eight were female (21.1%), 30 were male (78.9%), and the mean age was 66 ± 4.09. Thirty-two (84.21%) of the patients were operated on under general anesthesia and six (15.78%) under regional anesthesia. A shunt was used in 19 patients. Right carotid endarterectomy was performed in 20 cases and left carotid endarterectomy in 18 cases. We used the primary closure technique in two of 38 cases and patches on 36 of them. We used Dacron in 21 cases, PTFE in 12 cases, and saphenous vein as a patch in three cases. In the WMS digit spam and recall scores, the postoperative period fell on the 2nd day, and then on the 4th and 30th day after the operation, there was a low level of increase over time. Compared with the preoperative period, the learning score was found to be the lowest on the 2nd day, lower on the 4th day compared with the preoperative period and improved compared with the preoperative period on the 30th day. There was no decrease in the verbal fluency test score results after the operation, on the contrary, it was observed minimally. The test score results cumulatively were decreased in the early postoperative periods compared with the preoperative period and increased on the 30th day compared with the preoperative period. CONCLUSION: The purpose of CEA in the past was the prevention of ischemic stroke and cerebrovascular disease (CVD) rather than neurocognitive recovery. Factors affecting neurocognition in CEA are multifactorial. Preservation and improvement of neurocognition are more important than any other period of history. By prioritizing cognitive abilities in the treatment of carotid stenosis, individualization of the treatment will help maximize the increase in cognitive abilities by providing optimum benefit to the patient of each factor.

Long-term effects of experimental carotid stenosis on hippocampal infarct pathology, neurons and glia and amelioration by environmental enrichment.

Hippocampal atrophy and pathology are common in ageing-related disorders and associated with cognitive impairment and dementia. We explored whether environmental enrichment (EE) ameliorated the pathological sequelae in the hippocampus subsequent to chronic cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS). Seventy-four male C57BL/6 J mice underwent BCAS or sham surgery. One-week after surgery, mice were exposed to three different degrees of EE; either standard housing conditions (std), limited 3 -h exposure to EE per day (3 h) or full-time exposure to EE (full) for 3 months. Four months after surgery, the hippocampus was examined for the extent of vascular brain injury and neuronal and glial changes. Results showed that long-term BCAS induced strokes, most often in CA1 subfield, reduced 40-50 % CA1 neurons (P < 0.01) and increased microglia/macrophage in CA1-CA3 subfields (P < 0.02). Remarkably, both 3 h and full-time EE regimes attenuated hippocampal neuronal death and repressed recurrent strokes with complete prevention of larger infarcts in mice on full-time EE (P < 0.01). Full-time EE also reduced astrocytic clasmatodendrosis and microglial/macrophage activation in all CA subfields. Our results suggest that exposure to EE differentially reduces long-term hypoperfusive hippocampal damage. The implementation of even limited EE may be beneficial for patients diagnosed with vascular cognitive impairment.

Roles of GABAA receptor α5 subunit on locomotion and working memory in transient forebrain ischemia in mice.

The γ-aminobutyric acid A (GABAA) receptor, which contains a chloride channel, is a typical inhibitory neurotransmitter receptor in the central nervous system. Although the GABAergic neurotransmitter system has been discovered to be involved in various psychological behaviors, such as anxiety, convulsions, and cognitive function, its functional changes under conditions of ischemic pathological situation are still uncovered. In the present study, we attempted to elucidate the functional changes in the GABAergic system after transient forebrain ischemia in mice. A bilateral common carotid artery occlusion for 20 min was used to establish a model of transient forebrain ischemia/reperfusion (tI/R). Delayed treatment with diazepam, a positive allosteric modulator of the GABAA receptor, increased locomotor activity in the open field test and spontaneous alternations in the Y-maze test in tI/R mice, but not in shams. Delayed treatment with diazepam did not alter neuronal death or the number of GABAergic neurons in tI/R mice. However, tI/R induced changes in the protein levels of GABAA receptor subunits in the hippocampus. In particular, the most marked increase in the tI/R group was found in the level of α5 subunit of the GABAA receptor. Similar to delayed treatment with diazepam, delayed treatment with imidazenil, an α5-sensitive benzodiazepine, increased spontaneous alternations in the Y-maze in tI/R mice, whereas zolpidem, an α5-insensitive benzodiazepine, failed to show such effects. These results suggest that tI/R-induced changes in the level of the α5 subunit of the GABAA receptor can alter the function of GABAergic drugs in a mouse model of forebrain ischemia.

Cognitive Impairment Correlates Linearly with Mean Flow Velocity by Transcranial Doppler below a Definable Threshold.

INTRODUCTION: Low cerebral blood flow can affect cognition in patients with high-grade asymptomatic internal carotid artery stenosis. Current clinical algorithms use stroke risk to determine which patients should undergo revascularization without considering cognitive decline. Although correlations between low-flow and cognitive impairment have been reported, it is not known whether a threshold exists below which such a correlation expresses itself. Such information would be critical in treatment decisions about whether to intervene in patients with high-grade carotid artery stenosis who are at risk for cognitive decline. OBJECTIVE: To determine how reduced blood flow correlates with lower cognitive scores. METHODS: Patients with ≥80% unilateral internal carotid artery stenosis with no history of stroke were recruited from inpatient and outpatient practices at a single, large, comprehensive stroke center. Patients underwent bilateral insonation of middle cerebral arteries with standard 2-Hz probes over the temporal windows with transcranial Doppler. Cognitive assessments were performed by an experienced neuropsychologist using a cognitive battery comprising 14 standardized tests with normative samples grouped by age. Z-scores were generated for each test and averaged to obtain a composite Z-score for each patient. Multivariable linear regression examined associations between mean flow velocity (MFV) and composite Z-score, adjusting for age, education, and depression. The Davies test was used to determine if there was a breakpoint for a non-zero difference in slope of a segmented relationship over the range of composite Z-score values. RESULTS: Forty-two patients with unilateral high-grade internal carotid artery stenosis without stroke were enrolled (26 males, age = 74 ± 9 years, education = 16 ± 3 years). Average composite Z-score was -0.31 SD below the age-specific normative mean (range -2.8 to +1.2 SD). In linear regression adjusted for age, education, and depression, MFV correlated with cognitive Z-score (ß = 0.308, p = 0.043). A single breakpoint in the range of composite Z-scores was identified at 45 cm/s. For MFV <45 cm/s, Z-score decreased 0.05 SD per cm/s MFV (95% CI: 0.01-0.10). For MFV >45 cm/s, Z-score change was nonsignificant (95% CI: -0.07 to 0.05). CONCLUSIONS: In high-grade, asymptomatic carotid artery stenosis, cognitive impairment correlated linearly with lower flow in the hemisphere fed by the occluded internal carotid artery, but only below a threshold of MFV = 45 cm/s. Identifying a hemodynamic threshold for cognitive decline using a simple, noninvasive method may influence revascularization decision-making in otherwise "asymptomatic" carotid disease.

Carotid Revascularization and Its Effect on Cognitive Function: A Prospective Nonrandomized Multicenter Clinical Study.

BACKGROUND: There is conflicting data on the effect of carotid revascularization on cognitive function. OBJECTIVE: To examine cerebral blood flow and cognitive function after carotid revascularization. METHODS: Patients with unilateral, asymptomatic hemodynamically significant carotid artery stenosis (80% by computed tomography angiography or magnetic resonance angiography) were eligible. Cerebral blood flow was measured preoperatively and 1 month postoperatively using quantitative phase contrast magnetic resonance angiography. Preoperative flow impairment was defined as ipsilateral flow at least 20% less than contralateral flow (ie, an ipsilateral and/or contralateral flow ratio ≤0.8). Significant improvement in blood flow was defined as at least a 0.15 increase in flow ratio from pre- to postoperative. A control group was managed medically. Four cognitive domains were assessed at baseline, 1 month, and 6-12 months postoperatively. RESULTS: Seventy-five patients were enrolled at 6 sites; 53 carotid endarterectomy, 11 carotid artery stenting, and 11 medical management only controls. Preoperative Trails B scores were similar between groups. Revascularization was associated with significant improvement in executive function (Trials B) while no improvement was observed in controls (P = .007). Of patients with improvement in middle cerebral artery (MCA) flow, 90% had improved Trails B scores compared to 46.5% of patients without MCA flow improvement (P = .01). Greater absolute improvement in mean Trails B scores was observed in patients with MCA flow improvement compared to those without (48 seconds versus 24.7 seconds, P = .001). CONCLUSIONS: In a cohort of patient with asymptomatic carotid stenosis, improvement in MCA flow following carotid revascularization is associated with improvement in executive functioning.

Normalization of reduced functional connectivity after revascularization of asymptomatic carotid stenosis.

Internal carotid artery stenosis is a risk factor for ischemic stroke. Even in the absence of visible structural brain changes, patients with asymptomatic stenosis are prone to cognitive impairment. On a neuronal level, it was suggested that stenosis may lead to disturbed functional brain connectivity. If so, carotid revascularization should have an effect on hypothesized brain network disturbances. We studied functional connectivity in a motor network by resting-state electroencephalography in 12 patients with high grade asymptomatic carotid stenosis before and after interventional or surgical revascularization as compared to 23 controls. In patients with stenosis, functional connectivity of neural oscillations was significantly decreased prior and improved returning to normal connectivity after revascularization. In a subgroup of patients, also studied by contrast perfusion magnetic resonance imaging, reduced connectivity was associated with decreased regional brain perfusion reflected by increased mean transit time in the middle cerebral artery borderzone. Cognitive testing revealed only minor differences between patients and controls. In summary, we identified oscillatory connectivity changes in patients with asymptomatic carotid stenosis correlating with regional hypoperfusion, which both normalized after revascularization. Hence, electrophysiological changes might be a reversible precursor preceding macroscopic structural brain damage and behavioral impairment in patients with asymptomatic carotid stenosis.

Neurocognitive Changes After Carotid Revascularization According to Perfusion Parameters: A Meta-analysis of Current Literature.

BACKGROUND: Although the clinical outcomes continue to be scrutinized, there are a few data summarizing the changes in perfusion parameters in postoperative patients. The objective was to undertake a systematic literature review and perform a meta-analysis to assess the effects of cerebral perfusion changes in cognitive and functional status. METHODS: A systematic search was conducted in July 2018 identifying articles comparing perfusion parameter changes before and after carotid revascularization in patients with carotid artery stenosis. Combined overall effect sizes were calculated using random-effects models. RESULTS: The literature search identified 1031 unique articles eligible for analysis. Sixteen studies including 755 patients were identified. The studies were different for many methodological factors, for example, sample size, type of patients, statistical measure, type of test, timing of assessment, and so on. There were no differences in cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO2), and relative cerebral blood volume (rCBV) between preintervention and postintervention, but there was a significant increase of cerebral blood flow (CBF) (95% confidence interval [CI] standardized mean difference [Std. MD] : -0.83 [-1.27, -0.40]; P = 0.0002; I2 = 68%) and relative cerebral blood flow (rCBF) (95% CI Std. MD: -0.72 [-1.61, -0.27]; P < 0.0001; I2 = 48%) after operation. In addition, the perfusion of mean transit time (MTT) (95% CI Std. MD: 1.26 [0.62, 1.90]; P = 0.0001; I2 = 84%), oxygen extraction fraction (OEF) (95% CI Std. MD: 0.78 [0.24, 1.33]; P = 0.005; I2 = 0%), time to peak (TTP) (95% CI Std. MD: 0.46 [0.16, 0.77]; P = 0.003; I2 = 47%), and relative mean transit time (rMTT) (95% CI Std. MD: 0.41 [0.33, 0.50]; P < 0.00001; I2 = 67%) was higher before than after operation. CONCLUSIONS: The increase in changes in CBF and rCBF and the decrease in MTT, OEF, TTP, and rMTT after operation may indicate the improvement of cognition in the short term. Intraoperative perfusion parameters could be an important adjuvant monitoring method in neurocognitive changes after carotid revascularization.

Internal carotid artery occlusion may affect long-term quality of life in patients with high-flow carotid cavernous fistulas.

PURPOSE: To investigate the mid- and long-term effects of parent artery occlusion on the carotid cavernous fistula and on the quality of life of patients. MATERIALS AND METHODS: One hundred and twenty-six patients with high-flow direct carotid cavernous fistulas were enrolled. The modified Rankin scale scores, the headache impact test and the short form health survey scores were used to evaluate the patients' clinical status. RESULTS: Fifty-two patients had parent artery occlusion, while the rest of the 74 patients had embolization of carotid cavernous fistulas with parent artery preservation. No periprocedural complications occurred. Eighteen patients in the parent artery occlusion group had low perfusion symptoms within two weeks following embolization, and three patients had Horner's syndrome on the ipsilateral side. At two months' follow-up, the patients with parent artery occlusion had a significantly (P < 0.05) greater proportion of headache than patients with parent artery preservation. At 12 months, no significant (P > 0.05) difference existed in the headache impact test scores in both groups. At 36 months' follow-up, the patients with parent artery occlusion had decreased SF-30 scores in all the eight health domains compared with patients treated with parent artery preservation, with a significant (P < 0.05) lower score in general health, vitality and bodily pain in the parent artery occlusion compared with the parent artery preservation group. No recurrence was shown in patients with parent artery occlusion, but nine (12.2%) patients were recurrent in patients with parent artery preservation. CONCLUSION: Parent artery occlusion may affect the quality of life of patients with carotid cavernous fistulas despite being an effective treatment option for high-flow direct fistulas.

Effect of Unilateral Carotid Artery Stenting on Cognitive Function in Patients with Severe Bilateral Stenosis.

CASE DESCRIPTION: An 82-year-old man with dementia, gait disturbance, and a small cerebral infarction owing to severe bilateral carotid artery stenosis was successfully treated with carotid artery stenting (CAS). Preoperative cerebral vascular reactivity was reduced in the bilateral cerebral hemispheres. We performed CAS to treat right internal carotid artery stenosis. Following CAS, cerebral vascular reactivity showed an increase in the bilateral cerebral hemispheres. Memory, fluency, and attention also showed improvement. CONCLUSIONS: This case illustrates the potential benefit of single-stage CAS for cognitive function in severe bilateral carotid artery stenosis without hyperperfusion syndrome.

Severe asymptomatic carotid stenosis is associated with robust reductions in homotopic functional connectivity.

Severe (>70% narrowing) asymptomatic carotid stenosis (SACS) is associated with cognitive impairment and future strokes, and connectivity basis for the remote brain consequences is poorly understood. Here we explored homotopic connectivity and parenchymal lesions measured by multimodal magnetic resonance imaging (MRI) parameters in patients with SACS. Twenty-four patients with SACS (19 males/5 females; 64.25 ± 7.18 years), 24 comorbidities-matched controls (19 males/5 females; 67.16 ± 6.10 years), and an independent sample of elderly healthy controls (39 females/45 males; 57.92 ± 4.94 years) were included. Homotopic functional connectivity (FC) of resting-state functional MRI and structural connectivity (SC) of deterministic tractography were assessed. Arterial spin labeling based cerebral perfusion, susceptibility weighted imaging based microhemorrhagic lesions, and T2-weighted white matter hyperintensities were also quantified. Significant and robust homotopic reductions (validated by the independent dataset and support vector machine-based machine learning) were identified in the Perisylvian fissure in patients with SACS (false discovery rate corrected, voxel p < 0.05). These involved regions span across several large-scale brain systems, which include the somatomotor, salience, dorsal attention, and orbitofrontal-limbic networks. This significantly reduced homotopic FC can be partially explained by the corrected white matter hyperintensity size. Further association analyses suggest that the decreased homotopic FC in these brain regions is most closely associated with delayed memory recall, sensorimotor processing, and other simple cognitive functions. Together, these results suggest that SACS predominately affects the lower-order brain systems, while higher-order systems, especially the topographies of default mode network, are least impacted initially, but may serve as a hallmark precursor to vascular dementia. Thus, assessment of homotopic FC may provide a means of noninvasively tracking the progression of downstream brain damage following asymptomatic carotid stenosis.