The Role of White Matter Damage in the Risk of Periprocedural Diffusion-Weighted Lesions after Carotid Artery Stenting.

BACKGROUND: White matter hyperintensities (WMH) are a common finding in aged individuals affected by carotid artery disease and are a risk factor for first-ever and recurrent stroke. We investigated if white matter damage increases the risk of brain microembolism during carotid artery stenting (CAS), as evaluated by the appearance of new areas of restricted diffusion on diffusion-weighted images (DWI). METHODS: We evaluated 47 patients with severe internal carotid artery (ICA) stenosis undergoing CAS, comparing preprocedural clinical, ultrasound and radiological characteristics. WMH volume was computed on FLAIR images before CAS. After CAS, the DWI scan was looked over for areas of restricted diffusion (DWI lesions). A first univariate analysis was adopted to compare groups according to the occurrence of DWI lesions. Then, the variable DWI lesion was modelled by means of a logistic regression model. RESULTS: Seventeen patients developed at least 1 DWI lesion after CAS. Compared with non-DWI, DWI patients were more commonly treated in the left ICA (p = 0.007) and had a more severe WMH damage (p = 0.027). Indeed, the risk of a DWI lesion was higher in left versus right stenosis (OR = 9.0, 95% CI 1.9-42.7, p = 0.005) and increased for each log-unit of WMH lesion load (OR = 7.05, 95% CI 1.07-46.49, p = 0.042). A WMH lesion load of at least 5.25 cm3 had a 50% probability of occurrence of a new DWI lesion. CONCLUSIONS: Treated side and preexisting white matter damage are risk conditions for brain microembolism during CAS. This should be taken into account to optimize severe carotid artery disease management.

Cortical ischemic lesion burden measured by DIR is related to carotid artery disease severity.

BACKGROUND: Over time, exposure to cerebrovascular risk factors and carotid artery disease may cause multiple asymptomatic brain cortical and subcortical microinfarcts, which are commonly found at brain autopsy. So far, lack of convenient neuroimaging tools limited the investigation of grey matter ischemic damage in vivo. We applied the Double Inversion Recovery (DIR) sequence to explore the impact of carotid artery disease on intracortical ischemic lesion load in vivo, taking into account the impact of demographic characteristics and vascular risk factors. METHODS: DIR was acquired in 62 patients with common cerebrovascular risk factors stratified in three groups according to carotid artery disease severity. Intracortical lesions scored on DIR (DIRlns) were classified by vascular territory, lobe and hemisphere. White matter hyperintensities (WMHs) volume was also quantified on Fluid Attenuated Inversion Recovery sequence (FLAIR). RESULTS: Among demographic characteristics and cerebrovascular risk variables explored, General Linear Model indicated that age and carotid artery disease were significantly associated to DIRlns. After correcting for age, DIRlns load was found to be significantly dependent on carotid artery stenosis severity (F(2, 58) = 5.56, p = 0.006). A linear positive correlation between DIRlns and WMHs was found after correcting for age (p = 0.003). CONCLUSIONS: Carotid disease severity is associated with DIRlns accrual. Microembolism and impaired cerebral hemodynamics may act as physiopathological mechanisms underlying cortical ischemic damage. The role of other factors, such as small vessel disease and the possible interaction with carotid disease, remains to be further explored.

Hypercapnia affects the functional coupling of resting state electroencephalographic rhythms and cerebral haemodynamics in healthy elderly subjects and in patients with amnestic mild cognitive impairment.

OBJECTIVE: Cerebral vasomotor reactivity (VMR) and coherence of resting state electroencephalographic (EEG) rhythms are impaired in Alzheimer's disease (AD) patients. Here we tested the hypothesis that these two variables could be related. METHODS: We investigated VMR and coherence of resting state EEG rhythms in nine normal elderly (Nold) and in 10 amnesic mild cognitive impairment (MCI) subjects. Resting state eyes-closed EEG data were recorded at baseline pre-CO2 (ambient air, 2 min), during 7% CO2/air mixture inhalation (hypercapnia, 90 s) and post-CO2 (ambient air, 2 min) conditions. Simultaneous frontal bilateral near-infrared spectroscopy (NIRS) was performed to assess VMR by cortical oxy- and deoxy-haemoglobin concentration changes. EEG coherence across all electrodes was computed at delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), beta 2 (20-30 Hz) and gamma (30-40 Hz) bands. RESULTS: In Nold subjects, 'total coherence' of EEG across all frequency bands and electrode pairs decreased during hypercapnia, with full recovery during post-CO2. Total coherence resulted lower in pre-CO2 and post-CO2 and presented poor reactivity during CO2 inhalation in MCI patients compared with Nold subjects. Hypercapnia increased oxy-haemoglobin and decreased deoxy-haemoglobin concentrations in both groups. Furthermore, the extent of changes in these variables during CO2 challenge was correlated with the EEG coherence, as a reflection of neurovascular coupling. CONCLUSIONS: Hypercapnia induced normal frontal VMR that was detected by NIRS in both Nold and amnesic MCI groups, while it produced a reactivity of global functional coupling of resting state EEG rhythms only in the Nold group. SIGNIFICANCE: In amnesic MCI patients, global EEG functional coupling is basically low in amplitude and does not react to hypercapnia.

Diffusion-weighted lesions after carotid artery stenting are associated with cognitive impairment.

The effect of carotid artery stenting (CAS) on cognitive function is still debated. Cerebral microembolism, detectable by post-procedural diffusion-weighted imaging (DWI) lesions, has been suggested to predispose to cognitive decline. Our study aimed at evaluating the effect of CAS on cognitive profile focusing on the potential role of cerebral microembolic lesions, taking into consideration the impact of factors potentially influencing cognitive status (demographic features, vascular risk profile, neuropsychological evaluation at baseline and magnetic resonance (MR) markers of brain structural damage). Thirty-seven patients with severe carotid artery stenosis were enrolled. Neurological assessment, neuropsychological evaluation and brain MR were performed the day before CAS (E0). Brain MR with DWI was repeated the day after CAS (E1), while neuropsychological evaluation was done after a 14-month median period (E2). Volumes of both white matter hyperintensities and whole brain were estimated at E0 on axial MR FLAIR and T1w-SE sequences, respectively. Unadjusted ANOVA analysis showed a significant CAS*DWI interaction for MMSE (F=7.154(32), p=.012). After adjusting for factors potentially influencing cognitive status CAS*DWI interaction was confirmed for MMSE (F=7.092(13), p=.020). Patients with DWI lesions showed a mean E2-E0 MMSE reduction of -3.1, while group without DWI lesions showed a mean E2-E0 MMSE of +1.1. Our study showed that peri-procedural brain microembolic load impacts negatively on cognitive functions, independently from the influence of patients-related variables.

Cortical neuromodulation modifies cerebral vasomotor reactivity.

BACKGROUND AND PURPOSE: Cerebral vasomotor reactivity (VMR) is a capability of cerebral vessels to dilate in response to hypercapnia. Transcranial direct current stimulation (tDCS) effects on cerebral hemodynamics have been poorly studied. METHODS: Ten healthy subjects underwent anodal/cathodal tDCS on the left motor cortex. Before and after tDCS, VMR assessment by transcranial Doppler and an electrocardiogram were performed. Normalized low-frequency band power of heart rate variability and its reactivity from basal to VMR condition (LFN(react)) were estimated as relative markers of sympathetic activation. tDCS exerted a polarity-specific effect on both VMR (P=0.0001) and LFN(react) (P=0.001). Anodal tDCS decreased VMR by 3.4%/mm Hg CO(2) bilaterally and increased LFN(react), whereas cathodal tDCS increased VMR by 0.8%/mm Hg CO(2) bilaterally and reduced LFN(react). CONCLUSIONS: Cerebral VMR is modified by tDCS. Based on the consensual changes with heart rate variability, we can hypothesize that the sympathetic nervous system could modulate the bihemispheric modification of VMR. Further studies are needed to confirm this hypothesis.

Is there a role of near-infrared spectroscopy in predicting the outcome of patients with carotid artery occlusion?

BACKGROUND: Transcranial Doppler (TCD) studies demonstrated that cerebral vasomotor reactivity (VMR) can predict the outcome of carotid artery occlusion (CAO). Near-infrared spectroscopy (NIRS) is a non-invasive optical method for assessing hemoglobin (Hb) oxygenation parameters. The purpose of this study was to evaluate the role of NIRS parameters as prognostic markers of stroke occurrence in patients with CAO. METHODS: Sixty-five patients (46 men, mean age 68.8 years) with CAO were enrolled. Forty-two patients had previous cerebrovascular events (15 TIA, 27 minor stroke), the remaining 23 were asymptomatic. All subjects underwent simultaneous TCD and NIRS examination at rest and after hypercapnia. All patients completed follow-up (median, 36 months). RESULTS: During follow-up, 11 strokes occurred. Cerebral VMR measured by TCD had a prognostic role in stroke occurrence (p=0.042). The increase in Hb oxygen saturation detected by NIRS during hypercapnia predicted the occurrence of new cerebrovascular events, although without an overt significance (p=0.058). Hb oxygen saturation at rest, however, failed to be of prognostic value (p=0.65). CONCLUSIONS: NIRS is potentially useful in monitoring cerebral oxygenation; however, at present NIRS does not effectively predict the outcomes of stroke or vascular death in patients with CAO. This study does confirm the primary role of TCD VMR in the outcome of carotid disease.

Ceruloplasmin/Transferrin system is related to clinical status in acute stroke.

BACKGROUND AND PURPOSE: In acute stroke, Iron (Fe) may amplify reperfusion injury by catalyzing the conversion of superoxide and hydrogen peroxide into highly reactive radicals. Transferrin (Tf) is the main protein regulating Fe homeostasis, whereas Ceruplasmin (CP) is a circulating ferroxidase enzyme able to oxidize ferrous ions to less toxic ferric forms. This study aims at investigating whether CP, Copper (Cu), Tf, and Fe play a role in the pathophysiology of acute stroke. METHODS: We enrolled 35 acute stroke patients and 44 controls. All patients underwent: neurological examination assessed by National Institutes of Health Stroke Scale (NIHSS), ultrasound evaluation of carotid atherosclerosis, brain MRI to quantify ischemic lesion volume and measurement of serum levels of CP, Cu, Tf, Fe, hydro-peroxides, and Total plasmatic antioxidant capacity. RESULTS: In patients, NIHSS scores were associated with Tf (r=-0.48, P=0.004), hydro-peroxides (r=0.34, P=0.046), CP (r=0.43, P=0.012), and lesion volume (r=0.50, P=0.004). Lesion volume was inversely associated with Tf (r=-0.44, P=0.012). CP and hydro-peroxides were also largely related (r=0.81, P<0.001). The model multiple R was 0.57, resulting in a 32.5% of explained NIHSS variance with Tf accounting for 23.4% and CP for 9.1%. CONCLUSIONS: CP and Tf levels are representative of clinical status in acute stroke patients. Our findings suggest a protective role of Tf in acute stroke and a possible ambivalent role of CP.

fMRI-vs-MEG evaluation of post-stroke interhemispheric asymmetries in primary sensorimotor hand areas.

Growing evidence emphasizes a positive role of brain ipsilesional (IL) reorganization in stroke patients with partial recovery. Ten patients affected by a monohemispheric stroke in the middle cerebral artery territory underwent functional magnetic resonance (fMRI) and magnetoencephalography (MEG) evaluation of the primary sensory (S1) activation via the same paradigm (median nerve galvanic stimulation). Four patients did not present S1 fMRI activation [Rossini, P.M., Altamura, C., Ferretti, A., Vernieri, F., Zappasodi, F., Caulo, M., Pizzella, V., Del Gratta, C., Romani, G.L., Tecchio, F., 2004. Does cerebrovascular disease affect the coupling between neuronal activity and local haemodynamics? Brain 127, 99-110], although inclusion criteria required bilateral identifiable MEG responses. Mean Euclidean distance between fMRI and MEG S1 activation Talairach coordinates was 10.1+/-2.9 mm, with a 3D intra-class correlation (ICC) coefficient of 0.986. Interhemispheric asymmetries, evaluated by an MEG procedure independent of Talairach transformation, were outside or at the boundaries of reference ranges in 6 patients. In 3 of them, the IL activation presented medial or lateral shift with respect to the omega-shaped post-rolandic area while in the other 3, IL areas were outside the peri-rolandic region. In conclusion, despite dissociated intensity, the MEG and fMRI activations displayed good spatial consistency in stroke patients, thus confirming excessive interhemispheric asymmetries as a suitable indicator of unusual recruitments in the ipsilesional hemisphere, within or outside the peri-rolandic region.

Hemoglobin oxygen saturation as a marker of cerebral hemodynamics in carotid artery occlusion: an integrated transcranial doppler and near-infrared spectroscopy study.

Cerebral hemodynamics play a pivotal role in stroke pathogenesis. Transcranial Doppler (TCD) studies demonstrated the importance of cerebral vasomotor reactivity (VMR) on the outcome of carotid artery occlusion (CAO). So far, positron emission tomography represents the best technique for detecting both hemodynamic and metabolic aspects of cerebral perfusion adaptive processes in cerebrovascular patients. Near-infrared spectroscopy (NIRS) is a new method allowing for a non-invasive assessment of cerebral blood flow and hemoglobin (Hb) oxygenation parameters.A recent TCD and NIRS study demonstrated that patients with symptomatic CAO had lower VMR values measured by TCD and lower oxygen saturation (oxygen%) increases detected by NIRS than asymptomatic ones. The parameters were obtained simultaneously after CO(2) inhalation. The present study aims to investigate if Hb oxygen % could represent also at rest a marker of hemodynamic status in carotid disease.Thirty-five symptomatic and 17 asymptomatic patients with CAO underwent a simultaneous examination by means of TCD and NIRS at rest condition and during CO(2) reactivity test. Symptomatic patients presented with oxygen% values at rest higher (p = 0.001) and VMR values lower (p < 0.001) than asymptomatic subjects. According to a logistic model, for each unitary VMR increase, the odds of being symptomatic decreases of about 10% (OR = 0.9, p = 0.001); for each unitary increase of oxygen% at baseline, this odd increases of about 23% (OR = 1.23, p = 0.031). In addition to TCD VMR values, oxygen hemoglobin saturation at rest detected by NIRS can discriminate symptomatic from asymptomatic patients with CAO. NIRS can add an important contribution to explain pathophysiological mechanisms of stroke occurrence.

Markers of lacunar stroke in patients with moderate internal carotid artery stenosis.

The benefits of surgical correction of moderate internal carotid artery stenosis have been demonstrated only in symptomatic subjects. It is debatable whether patients with lacunar infarct ipsilateral to a moderate carotid stenosis may be considered symptomatic like those with large-artery stroke. The aim of the study was to seek markers capable of differentiating patients with lacunar or non-lacunar stroke ipsilateral to a moderate internal carotid artery stenosis. We enrolled 95 patients with a first stroke ipsilateral to a moderate (50-69 %) stenosis of the internal carotid artery and divided them into lacunar and non-lacunar stroke based on clinical presentation and neuroradiological findings; 34 subjects with asymptomatic moderate carotid stenosis and 31 normal individuals were also studied. Baseline characteristics; risk factors, cerebrovascular reactivity to hypercapnia evaluated by means of the breath-holding index (BHI), the presence and severity of carotid stenosis and intimamedia thickness (IMT) of the common carotid arteries were determined. There were 36 patients with lacunar and 59 with non-lacunar stroke. Degree of stenosis, and IMT and BHI ipsilateral to symptomatic stenosis were found to be significant independent predictors as each 10 % increase of stenosis carried a 4.3 higher probability of non-lacunar stroke (95 % CI: 1.91-9.51); each decimillimeter increment in IMT increased this probability by 1.45 (95 % CI: 1.10-1.92); and the risk odds ratio associated with each 0.1 increase in BHI was 1.88 (95 % CI: 1.33-2.66). A decrease in BHI of 0.1 thus carried a 90% greater probability of having a lacunar stroke. The results show that patients with moderate internal carotid artery stenosis and lacunar stroke can be differentiated from those with non-lacunar stroke on the basis of distinctive ultrasonographic findings. Further studies are needed to clarify whether our findings have pathogenetic implications and may be of help for the planning of different therapeutic strategies in patients with moderate internal carotid stenosis and lacunar or non-lacunar ipsilateral stroke.

Transcranial Doppler and near-infrared spectroscopy can evaluate the hemodynamic effect of carotid artery occlusion.

BACKGROUND AND PURPOSE: Cerebral hemodynamic and metabolic changes can compensate for the decrease in cerebral blood flow occurring in patients with carotid occlusive disease. At present, a complete assessment of the cerebral adaptive status is only possible with positron-emission tomography. Near-infrared spectroscopy (NIRS) is a noninvasive technique that, providing a real time assessment of fluctuations in cerebral hemoglobin, has been used to estimate the cerebral blood volume and to measure cerebral vasomotor reactivity (VMR). Moreover, NIRS technology, by allowing the absolute measurement of absorption and scattering coefficients of brain, can determine the oxyhemoglobin and deoxyhemoglobin concentrations in situ in the blood stream. METHODS: In order to evaluate different aspects of the cerebral hemodynamic status, 27 subjects with symptomatic and asymptomatic carotid artery occlusion and 30 healthy subjects underwent a simultaneous examination by means of transcranial Doppler (TCD), able to reliably detect collateral circulation and VMR, and NIRS at rest condition and during CO2 reactivity test. RESULTS: The main finding of this study was the demonstration of a difference between asymptomatic and symptomatic patients in terms of mean flow velocity increase (52.4% versus 21.0%; P<0.001) estimated by TCD and of hemoglobin saturation increase measured by NIRS (6.8% versus 3.8%; P=0.015). CONCLUSIONS: The opportunity to perform NIRS and TCD simultaneously provides useful information about both hemodynamic and metabolic cerebral adaptive status in patients with occlusive disease in a simple, noninvasive, and reliable way.

Early cerebral hemodynamic changes during passive movements and motor recovery after stroke.

Recovery from hemiplegia is a complex phenomenon that depends on various adaptive processes involving both the affected and the unaffected hemisphere. Our aim in this study was to investigate changes in cerebral perfusion in hemiplegic stroke patients during passive movements and their correlation with the subsequent motor recovery. The study included 30 patients with single, subcortical ischemic cerebral lesions. Within 14 days (range 8 to 14 days) from stroke onset, all patients were examined for the effects of passive elbow movements on cerebral blood flow in the middle cerebral arteries (MCAs) by means of bilateral transcranial Doppler (TCD) ultrasonography. On the same day as TCD assessment, they were also evaluated clinically with the Canadian Neurological Scale (CNS) and with Medical Research Council (MRC) scale for motor deficit of the affected arm. A clinical evaluation using the same scales was repeated after two months of motor rehabilitation therapy. We investigated the relationship between changes of Mean Flow Velocity (MFV) during passive movements and degree of recovery after stroke. The logistic regression procedure indicated that out of all factors considered as possibly related to a good clinical motor deficit recovery of the affected arm, evaluated by means of MRC, only the MFV percentage increase played a predictive role. In particular, for each additional point of contralateral MFV percentage increase during passive movement of the affected arm, the relative probability of good clinical recovery increased 5.68 times (95% CI=1.76-18.40; p=0.004). Similar results were found when the clinical recovery was measured by means of the CNS (slope=0.40, p<0.001). Passive movements in hemiplegic stroke patients before clinical recovery elicit activation patterns that may be critical for the restoration of motor function.I n particular, early and consistent activation of the affected hemisphere, as detected with TCD, seems to predict the positive evolution of a motor deficit.