Total cerebral blood flow, white matter lesions and brain atrophy: the SMART-MR study.

We investigated whether total cerebral blood flow (CBF) was associated with brain atrophy, and whether this relation was modified by white matter lesions (WML). Within the Second Manifestations of ARTerial disease-magnetic resonance (SMART-MR) study, a prospective cohort study among patients with arterial disease, cross-sectional analyses were performed in 828 patients (mean age 58+/-10 years, 81% male) with quantitative flow, atrophy, and WML measurements on magnetic resonance imaging (MRI). Total CBF was measured with MR angiography and was expressed per 100 mL brain volume. Total brain volume and ventricular volume were divided by intracranial volume to obtain brain parenchymal fraction (BPF) and ventricular fraction (VF). Lower BPF indicates more global brain atrophy, whereas higher VF indicates more subcortical brain atrophy. Mean CBF was 52.0+/-10.2 mL/min per 100 mL, mean BPF was 79.2+/-2.9%, and mean VF was 2.03+/-0.96%. Linear regression analyses showed that lower CBF was associated with more subcortical brain atrophy, after adjusting for age, sex, vascular risk factors, intima-media thickness, and lacunar infarcts, but only in patients with moderate to severe WML (upper quartile of WML): Change in VF per s.d. decrease in CBF 0.18%, 95% CI: 0.02 to 0.34%. Our findings suggest that cerebral hypoperfusion in the presence of WML may be associated with subcortical brain atrophy.     

Magnetic resonance imaging-based changes in vascular morphology and cerebral perfusion in subacute ischemic stroke

MRI-based vessel size imaging (VSI) allows for in-vivo assessment of cerebral microvasculature and perfusion. This exploratory analysis of vessel size (VS) and density (Q; both assessed via VSI) in the subacute phase of ischemic stroke involved sixty-two patients from the BAPTISe cohort (‘Biomarkers And Perfusion--Training-Induced changes after Stroke’) nested within a randomized controlled trial (intervention: 4-week training vs. relaxation). Relative VS, Q, cerebral blood volume (rCBV) and –flow (rCBF) were calculated for: ischemic lesion, perilesional tissue, and region corresponding to ischemic lesion on the contralateral side (mirrored lesion). Linear mixed-models detected significantly increased rVS and decreased rQ within the ischemic lesion compared to the mirrored lesion (coefficient[standard error]: 0.2[0.08] p = 0.03 and −1.0[0.3] p = 0.02, respectively); lesion rCBF and rCBV were also significantly reduced. Mixed-models did not identify time-to-MRI, nor training as modifying factors in terms of rVS or rQ up to two months post-stroke. Larger lesion VS was associated with larger lesion volumes (β 34, 95%CI 6.2–62; p = 0.02) and higher baseline NIHSS (β 3.0, 95%CI 0.49–5.3;p = 0.02), but was not predictive of six-month outcome. In summary, VSI can assess the cerebral microvasculature and tissue perfusion in the subacute phases of ischemic stroke, and may carry relevant prognostic value in terms of lesion volume and stroke severity.     

Endothelial progenitor cell transplantation alleviated ischemic brain injury via inhibiting C3/C3aR pathway in mice

Endothelial progenitor cell transplantation is a potential therapeutic approach in brain ischemia. However, whether the therapeutic effect of endothelial progenitor cells is via affecting complement activation is unknown. We established a mouse focal ischemia model (n = 111) and transplanted endothelial progenitor cells into the peri-infarct region immediately after brain ischemia. Neurological outcomes and brain infarct/atrophy volume were examined after ischemia. Expression of C3, C3aR and pro-inflammatory factors were further examined to explore the role of endothelial progenitor cells in ischemic brain. We found that endothelial progenitor cells improved neurological outcomes and reduced brain infarct/atrophy volume after 1 to 14 days of ischemia compared to the control (p < 0.05). C3 and C3aR expression in the brain was up-regulated at 1 day up to 14 days (p < 0.05). Endothelial progenitor cells reduced astrocyte-derived C3 (p < 0.05) and C3aR expression (p < 0.05) after ischemia. Endothelial progenitor cells also reduced inflammatory response after ischemia (p < 0.05). Endothelial progenitor cell transplantation reduced astrocyte-derived C3 expression in the brain after ischemic stroke, together with decreased C3aR and inflammatory response contributing to neurological function recovery. Our results indicate that modulating complement C3/C3aR pathway is a novel therapeutic target for the ischemic stroke.     

DSC perfusion-based collateral imaging and quantitative T2 mapping to assess regional recruitment of leptomeningeal collaterals and microstructural cortical tissue damage in unilateral steno-occlusive vasculopathy

Leptomeningeal collateral supply is considered pivotal in steno-occlusive vasculopathy to prevent chronic microstructural ischaemic tissue damage. The aim of this study was to assess the alleged protective role of leptomeningeal collaterals in patients with unilateral high-grade steno-occlusive vasculopathy using quantitative (q)T2 mapping and perfusion-weighted imaging (PWI)-based collateral abundance. High-resolution qT2 was used to estimate microstructural damage of the segmented normal-appearing cortex. Volumetric abundance of collaterals was assessed based on PWI source data. The ratio relative cerebral blood flow/relative cerebral blood volume (rCBF/rCBV) as a surrogate of relative cerebral perfusion pressure (rCPP) was used to investigate the intravascular hemodynamic competency of pial collateral vessels and the hemodynamic state of brain parenchyma. Within the dependent vascular territory with increased cortical qT2 values (P = 0.0001) compared to the contralateral side, parenchymal rCPP was decreased (P = 0.0001) and correlated negatively with increase of qT2 (P  < 0.05). Furthermore, volumetric abundance of adjacent leptomeningeal collaterals was significantly increased (P < 0.01) and negatively correlated with changes of parenchymal rCPP (P = 0.01). Microstructural cortical damage is closely related to restrictions of antegrade blood flow despite increased pial collateral vessel abundance. Therefore, increased leptomeningeal collateral supply cannot necessarily be regarded as a sign of effective compensation in patients with high-grade steno-occlusive vasculopathy.     

Repetitive mTBI is associated with age-related reductions in cerebral blood flow but not cortical thickness

Mild traumatic brain injury (mTBI) is a risk factor for Alzheimer’s disease (AD), and evidence suggests cerebrovascular dysregulation initiates deleterious neurodegenerative cascades. We examined whether mTBI history alters cerebral blood flow (CBF) and cortical thickness in regions vulnerable to early AD-related changes. Seventy-four young to middle-aged Veterans (mean age = 34, range = 23–48) underwent brain scans. Participants were divided into: (1) Veteran Controls (n = 27), (2) 1–2 mTBIs (n = 26), and (2) 3+ mTBIs (n = 21) groups. Resting CBF was measured using MP-PCASL. T1 structural scans were processed with FreeSurfer. CBF and cortical thickness estimates were extracted from nine AD-vulnerable regions. Regression analyses examined whether mTBI moderated the association between age, CBF, and cortical thickness. Regressions adjusting for sex and posttraumatic stress revealed mTBI moderated the association between age and CBF of the precuneus as well as superior and inferior parietal cortices (p’s < .05); increasing age was associated with lower CBF in the 3+ mTBIs group, but not in the VCs or 1–2 mTBIs groups. mTBI did not moderate associations between age and cortical thickness (p’s >.05). Repetitive mTBI is associated with cerebrovascular dysfunction in AD-vulnerable regions and may accelerate pathological aging trajectories.     

Cerebral arterial bolus arrival time is prolonged in multiple sclerosis and associated with disability

Alterations in the overall cerebral hemodynamics have been reported in multiple sclerosis (MS); however, their cause and significance is unknown. While potential venous causes have been examined, arterial causes have not. In this study, a multiple delay time arterial spin labeling magnetic resonance imaging sequence at 3T was used to quantify the arterial hemodynamic parameter bolus arrival time (BAT) and cerebral blood flow (CBF) in normal-appearing white matter (NAWM) and deep gray matter in 33 controls and 35 patients with relapsing–remitting MS. Bolus arrival time was prolonged in MS in NAWM (1.0±0.2 versus 0.9±0.2 seconds, P=0.031) and deep gray matter (0.90±0.18 versus 0.80±0.14 seconds, P=0.001) and CBF was increased in NAWM (14±4 versus 10±2 mL/100 g/min, P=0.001). Prolonged BAT in NAWM (P=0.042) and deep gray matter (P=0.01) were associated with higher expanded disability status score. This study demonstrates alteration in cerebral arterial hemodynamics in MS. One possible cause may be widespread inflammation. Bolus arrival time was longer in patients with greater disability independent of atrophy and T₂ lesion load, suggesting alterations in cerebral arterial hemodynamics may be a marker of clinically relevant pathology.     

Cerebral haemodynamics with head position changes post-ischemic stroke: A systematic review and meta-analysis

The effects of upright postures on the cerebral circulation early post-ischemic stroke are not fully understood. We conducted a systematic review and meta-analysis to investigate the effects of head positioning on cerebral haemodynamics assessed by imaging methods post-ischemic stroke. Of the 21 studies included (n = 529), 15 used transcranial Doppler. Others used near-infrared, diffuse correlation spectroscopy and nuclear medicine modalities. Most tested head positions between 0° and 45°. Seventeen studies reported changes in CBF parameters (increase at lying-flat or decrease at more upright) in the ischaemic hemisphere with position change. However, great variability was found and risk of bias was high in many studies. Pooled data of two studies ≤24 h (n = 28) showed a mean increase in cerebral blood flow (CBF) velocity of 8.5 cm/s in the ischaemic middle cerebral artery (95%CI,−2.2–19.3) from 30° to 0°. The increase found ≤48 h (n = 50) was of 2.3 cm/s (95%CI,−4.6–9.2), while ≤7 days (n = 38) was of 8.4 cm/s (95%CI, 1.8–15). Few very early studies (≤2 days) tested head positions greater than 30° and were unable to provide information about the response of acute stroke patients to upright postures (sitting, standing). These postures are part of current clinical practice and knowledge on their effects on cerebral haemodynamics is required.     

Blood flow distribution in cerebral arteries

High-resolution phase–contrast magnetic resonance imaging can now assess flow in proximal and distal cerebral arteries. The aim of this study was to describe how total cerebral blood flow (tCBF) is distributed into the vascular tree with regard to age, sex and anatomic variations. Forty-nine healthy young (mean 25 years) and 45 elderly (mean 71 years) individuals were included. Blood flow rate (BFR) in 21 intra- and extracerebral arteries was measured. Total cerebral blood flow was defined as BFR in the internal carotid plus vertebral arteries and mean cerebral perfusion as tCBF/brain volume. Carotid/vertebral distribution was 72%/28% and was not related to age, sex, or brain volume. Total cerebral blood flow (717±123 mL/min) was distributed to each side as follows: middle cerebral artery (MCA), 21% distal MCA, 6% anterior cerebral artery (ACA), 12%, distal ACA, 4% ophthalmic artery, 2% posterior cerebral artery (PCA), 8% and 20% to basilar artery. Deviating distributions were observed in subjects with ‘fetal'' PCA. Blood flow rate in cerebral arteries decreased with increasing age (P<0.05) but not in extracerebral arteries. Mean cerebral perfusion was higher in women (women: 61±8; men: 55±6 mL/min/100 mL, P<0.001). The study describes a new method to outline the flow profile of the cerebral vascular tree, including reference values, and should be used for grading the collateral flow system.     

Differential effects of ischemic vascular disease and Alzheimer’s disease on brain atrophy and cognition

We previously reported that pathologic measures of arteriosclerosis (AS), cerebral infarction, and Alzheimer’s disease (AD) are independently correlated with cortical gray matter (CGM) atrophy measured by in vivo magnetic resonance imaging (MRI). Here, we use path analyses to model the associations between these three pathology measures and cognitive impairment, as mediated by CGM atrophy, after controlling for age and education. In this sample of 116 elderly persons followed longitudinally to autopsy (ischemic vascular disease (IVD) program project), differential patterns were observed between AS and atrophy/cognition versus AD and atrophy/cognition. The total effect of AD pathology on global cognition (β = −0.61, s.e. = 0.06) was four times stronger than that of AS (β = −0.15, s.e. = 0.08). The effect of AS on cognition appears to occur through cerebral infarction and CGM atrophy (β = −0.13, s.e. = 0.04). In contrast, the effects of AD pathology on global cognition (β = −0.50, s.e. = 0.07) occur through a direct pathway that is five times stronger than the indirect pathway acting through CGM atrophy (β = −0.09, s.e. = 0.03). The strength of this direct AD pathway was not significantly mitigated by adding hippocampal volume to the model. AD pathology affects cognition not only through brain atrophy, but also via an unmeasured pathway that could be related to synaptic dysfunction before the development of cortical atrophy.     

Brain deep medullary veins on 3-T MRI in a population-based cohort

Our aim is to investigate whether vascular risk factors are associated with cerebral deep medullary veins (DMVs) and whether DMVs are associated with MRI markers of cerebral small vessel disease (CSVD) or risk of stroke. In a community-based cohort of 1056 participants (mean age 55.7 years), DMVs were identified on susceptibility-weighted imaging (SWI) and counted in periventricular regions. Neuroimaging markers including lacunes, whiter matter hyperintensity (WMH), microbleeds, enlarged perivascular space, and brain atrophy were evaluated. The number of DMVs decreased with age (p = 0.007). After adjusting for age and sex, the number of DMVs was not associated with traditional vascular risk factors. Fewer DMVs was associated with increase of WMH and lacunes, but the association vanished after adjustment for vascular risk factors. However, fewer DMVs were independently associated with brain atrophy (p < 0.001). DMVs were not associated with three-year risk of stroke. Our results suggest that DMV is significantly different from other MRI markers of CSVD regarding risk factors, association with other CSVD markers, and risk of stroke. Nonetheless, the significant association between DMV and brain atrophy suggested the potential role of venules in age-related neurodegenerative process, which deserves further investigation.     

Cerebral critical closing pressure and resistance-area product: the influence of dynamic cerebral autoregulation,age and sex

Instantaneous arterial pressure-flow (or velocity) relationships indicate the existence of a cerebral critical closing pressure (CrCP), with the slope of the relationship expressed by the resistance-area product (RAP). In 194 healthy subjects (20–82 years, 90 female), cerebral blood flow velocity (CBFV, transcranial Doppler), arterial blood pressure (BP, Finapres) and end-tidal CO₂ (EtCO₂, capnography) were measured continuously for five minutes during spontaneous fluctuations of BP at rest. The dynamic cerebral autoregulation (CA) index (ARI) was extracted with transfer function analysis from the CBFV step response to the BP input and step responses were also obtained for the BP-CrCP and BP-RAP relationships. ARI was shown to decrease with age at a rate of −0.025 units/year in men (p = 0.022), but not in women (p = 0.40). The temporal patterns of the BP-CBFV, BP-CrCP and BP-RAP step responses were strongly influenced by the ARI (p < 0.0001), but not by sex. Age was also a significant determinant of the peak of the CBFV step response and the tail of the RAP response. Whilst the RAP step response pattern is consistent with a myogenic mechanism controlling dynamic CA, further work is needed to explore the potential association of the CrCP step response with the flow-mediated component of autoregulation.     

Partial neural protection with prophylactic low-dose melatonin after asphyxia in preterm fetal sheep

Melatonin is a naturally occurring indolamine with mild antioxidant properties that is neuroprotective in perinatal animals. There is limited information on its effects on preterm brain injury. In this study, 23 chronically instrumented fetal sheep received 25 minutes of complete umbilical cord occlusion at 101 to 104 days gestation (term is 147 days). Melatonin was administered to the ewe 15 minutes before occlusion (0.1 mg/kg bolus followed by 0.1 mg/kg per hour for 6 hours, n=8), or the equivalent volume of vehicle (2% ethanol, n=7), or saline (n=8), or maternal saline plus sham occlusion (n=8). Sheep were killed after 7 days recovery in utero. Fetal blood pressure, heart rate, nuchal activity, and temperature were similar between groups. Vehicle infusion was associated with improved neuronal survival in the caudate nucleus, but greater neuronal loss in the regions of the hippocampus, with reduced proliferation and increased ameboid microglia in the white matter (P<0.05). Maternal melatonin infusion was associated with faster recovery of fetal EEG, prolonged reduction in carotid blood flow, similar neuronal survival to vehicle, improved numbers of mature oligodendrocytes, and reduced microglial activation in the white matter (P<0.05). Prophylactic maternal melatonin treatment is partially protective but its effects may be partly confounded by ethanol used to dissolve melatonin.     

Blood pressure and sodium: Association with MRI markers in cerebral small vessel disease

Dietary salt intake and hypertension are associated with increased risk of cardiovascular disease including stroke. We aimed to explore the influence of these factors, together with plasma sodium concentration, in cerebral small vessel disease (SVD). In all, 264 patients with nondisabling cortical or lacunar stroke were recruited. Patients were questioned about their salt intake and plasma sodium concentration was measured; brain tissue volume and white-matter hyperintensity (WMH) load were measured using structural magnetic resonance imaging (MRI) while diffusion tensor MRI and dynamic contrast-enhanced MRI were acquired to assess underlying tissue integrity. An index of added salt intake (P = 0.021), pulse pressure (P = 0.036), and diagnosis of hypertension (P = 0.0093) were positively associated with increased WMH, while plasma sodium concentration was associated with brain volume (P = 0.019) but not with WMH volume. These results are consistent with previous findings that raised blood pressure is associated with WMH burden and raise the possibility of an independent role for dietary salt in the development of cerebral SVD.     

MRI measurement of angiogenesis and the therapeutic effect of acute marrow stromal cell administration on traumatic brain injury

Using magnetic resonance imaging (MRI), the present study was undertaken to investigate the therapeutic effect of acute administration of human bone marrow stromal cells (hMSCs) on traumatic brain injury (TBI) and to measure the temporal profile of angiogenesis after the injury with or without cell intervention. Male Wistar rats (300 to 350 g, n=18) subjected to controlled cortical impact TBI were intravenously injected with 1 mL of saline (n=9) or hMSCs in suspension (n=9, 3 × 10⁶ hMSCs) 6 hours after TBI. In-vivo MRI acquisitions of T2-weighted imaging, cerebral blood flow (CBF), three-dimensional (3D) gradient echo imaging, and blood-to-brain transfer constant (Ki) of contrast agent were performed on all animals 2 days after injury and weekly for 6 weeks. Sensorimotor function and spatial learning were evaluated. Volumetric changes in the trauma-induced brain lesion and the lateral ventricles were tracked and quantified using T2 maps, and hemodynamic alteration and blood–brain barrier permeability were monitored by CBF and Ki, respectively. Our data show that transplantation of hMSCs 6 hours after TBI leads to reduced cerebral atrophy, early and enhanced cerebral tissue perfusion and improved functional outcome compared with controls. The hMSC treatment increases angiogenesis in the injured brain, which may promote neurologic recovery after TBI.     

Brain temperature regulation in poor-grade subarachnoid hemorrhage patients – A multimodal neuromonitoring study

Elevated body temperature (T_core) is associated with poor outcome after subarachnoid hemorrhage (SAH). Brain temperature (T_brain) is usually higher than T_core. However, the implication of this difference (T_delta) remains unclear. We aimed to study factors associated with higher T_delta and its association with outcome. We included 46 SAH patients undergoing multimodal neuromonitoring, for a total of 7879 h of averaged data of T_core, T_brain, cerebral blood flow, cerebral perfusion pressure, intracranial pressure and cerebral metabolism (CMD). Three-months good functional outcome was defined as modified Rankin Scale ≤2. T_brain was tightly correlated with T_core (r = 0.948, p < 0.01), and was higher in 73.7% of neuromonitoring time (T_delta +0.18°C, IQR −0.01 – 0.37°C). A higher T_delta was associated with better metabolic state, indicated by lower CMD-glutamate (p = 0.003) and CMD-lactate (p < 0.001), and lower risk of mitochondrial dysfunction (MD) (OR = 0.2, p < 0.001). During MD, T_delta was significantly lower (0°C, IQR −0.2 – 0.1; p < 0.001). A higher T_delta was associated with improved outcome (OR = 7.7, p = 0.002). Our study suggests that T_brain is associated with brain metabolic activity and exceeds T_core when mitochondrial function is preserved. Further studies are needed to understand how T_delta may serve as a surrogate marker for brain function and predict clinical course and outcome after SAH.     

Impaired response of cerebral oxygen metabolism to visual stimulation in Huntington’s disease

Huntington’s disease (HD) is a neurodegenerative disease caused by a CAG triplet repeat expansion in the Huntingtin gene. Metabolic and microvascular abnormalities in the brain may contribute to early physiological changes that subserve the functional impairments in HD. This study is intended to investigate potential abnormality in dynamic changes in cerebral blood volume (CBV) and cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO₂) in the brain in response to functional stimulation in premanifest and early manifest HD patients. A recently developed 3-D-TRiple-acquisition-after-Inversion-Preparation magnetic resonance imaging (MRI) approach was used to measure dynamic responses in CBV, CBF, and CMRO₂ during visual stimulation in one single MRI scan. Experiments were conducted in 23 HD patients and 16 healthy controls. Decreased occipital cortex CMRO₂ responses were observed in premanifest and early manifest HD patients compared to controls (P < 0.001), correlating with the CAG-Age Product scores in these patients (R² = 0.4, P = 0.001). The results suggest the potential value of this reduced CMRO₂ response during visual stimulation as a biomarker for HD and may illuminate the role of metabolic alterations in the pathophysiology of HD.     

The bidirectional association between reduced cerebral blood flow and brain atrophy in the general population

The question remains whether reduced cerebral blood flow (CBF) leads to brain atrophy or vice versa. We studied the longitudinal relation between CBF and brain volume in a community-dwelling population. In the Rotterdam Study, 3011 participants (mean age 59.6 years (s.d. 8.0)) underwent repeat brain magnetic resonance imaging to quantify brain volume and CBF at two time points. Adjusted linear regression models were used to investigate the bidirectional relation between CBF and brain volume. We found that smaller brain volume at baseline was associated with a steeper decrease in CBF in the whole population (standardized change per s.d. increase of total brain volume (TBV)=0.296 (95% confidence interval (CI) 0.200; 0.393)). Only in persons aged ⩾65 years, a lower CBF at baseline was associated with steeper decline of TBV (standardized change per s.d. increase of CBF=0.003 (95% CI −0.004; 0.010) in the whole population and 0.020 (95% CI 0.004; 0.036) in those aged ⩾65 years of age). Our results indicate that brain atrophy causes CBF to decrease over time, rather than vice versa. Only in persons aged >65 years of age did we find lower CBF to also relate to brain atrophy.     

Perfusion imaging-based tissue-level collaterals predict ischemic lesion net water uptake in patients with acute ischemic stroke and large vessel occlusion

Ischemic lesion Net Water Uptake (NWU) quantifies cerebral edema formation and likely correlates with the microvascular perfusion status of patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO). We hypothesized that favorable tissue-level collaterals (TLC) predict less NWU and good functional outcomes. We performed a retrospective multicenter analysis of AIS-LVO patients who underwent thrombectomy triage. TLC were measured on cerebral perfusion studies using the hypoperfusion intensity ratio (HIR; volume ratio of brain tissue with [Tmax > 10 sec/Tmax > 6 sec]); favorable TLC were regarded as HIR ≤ 0.4. NWU was determined using a quantitative densitometry approach on follow-up CT. Primary outcome was NWU. Secondary outcome was a good functional outcome (modified Rankin Scale [mRS] 0–2).580 patients met inclusion criteria. Favorable TLC (β: 4.23, SE: 0.65; p < 0.001) predicted smaller NWU after treatment. Favorable TLC (OR: 2.35, [95% CI: 1.31–4.21]; p < 0.001), and decreased NWU (OR: 0.75, [95% CI: 0.70–0.79]; p < 0.001) predicted good functional outcome, while controlling for age, glucose, CTA collaterals, baseline NIHSS and good vessel reperfusion status.We conclude that favorable TLC predict less ischemic lesion NWU after treatment in AIS-LVO patients. Favorable TLC and decreased NWU were independent predictors of good functional outcome.     

Cerebral cortical microinfarcts in patients with internal carotid artery occlusion

Cerebral cortical microinfarcts (CMI) are small ischemic lesions that are associated with cognitive impairment and probably have multiple etiologies. Cerebral hypoperfusion has been proposed as a causal factor. We studied CMI in patients with internal carotid artery (ICA) occlusion, as a model for cerebral hemodynamic compromise. We included 95 patients with a complete ICA occlusion (age 66.2 ± 8.3, 22% female) and 125 reference participants (age 65.5 ± 7.4, 47% female). Participants underwent clinical, neuropsychological, and 3 T brain MRI assessment. CMI were more common in patients with an ICA occlusion (54%, median 2, range 1–33) than in the reference group (6%, median 0; range 1–7; OR 14.3; 95% CI 6.2–33.1; p<.001). CMI were more common ipsilateral to the occlusion than in the contralateral hemisphere (median 2 and 0 respectively; p<.001). In patients with CMI compared to patients without CMI, the number of additional occluded or stenosed cervical arteries was higher (p=.038), and cerebral blood flow was lower (B −6.2 ml/min/100 ml; 95% CI −12.0:–0.41; p=.036). In conclusion, CMI are common in patients with an ICA occlusion, particularly in the hemisphere of the occluded ICA. CMI burden was related to the severity of cervical arterial compromise, supporting a role of hemodynamics in CMI etiology.     

Stroke-induced brain parenchymal injury drives blood–brain barrier early leakage kinetics: a combined in vivo/in vitro study

The disappointing clinical outcomes of neuroprotectants challenge the relevance of preclinical stroke models and data in defining early cerebrovascular events as potential therapeutic targets. The kinetics of blood–brain barrier (BBB) leakage after reperfusion and the link with parenchymal lesion remain debated. By using in vivo and in vitro approaches, we conducted a kinetic analysis of BBB dysfunction during early reperfusion. After 60 minutes of middle cerebral artery occlusion followed by reperfusion times up to 24 hours in mice, a non-invasive magnetic resonance imaging method, through an original sequence of diffusion-weighted imaging, determined brain water mobility in microvascular compartments (D*) apart from parenchymal compartments (apparent diffusion coefficient). An increase in D* found at 4 hours post reperfusion concurred with the onset of both Evans blue/Dextran extravasations and in vitro BBB opening under oxygen-glucose deprivation and reoxygenation (R). The BBB leakage coincided with an emerging cell death in brain tissue as well as in activated glial cells in vitro. The co-culture of BBB endothelial and glial cells evidenced a recovery of endothelium tightness when glial cells were absent or non-injured during R. Preserving the ischemic brain parenchymal cells within 4 hours of reperfusion may improve therapeutic strategies for cerebrovascular protection against stroke.