Dynamic monitoring of blood-brain barrier integrity using water exchange index (WEI) during mannitol and CO2 challenges in mouse brain.

The integrity of the blood-brain barrier (BBB) is critical to normal brain function. Traditional techniques for the assessment of BBB disruption rely heavily on the spatiotemporal analysis of extravasating contrast agents. However, such methods based on the leakage of relatively large molecules are not suitable for the detection of subtle BBB impairment or for the performance of repeated measurements in a short time frame. Quantification of the water exchange rate constant (WER) across the BBB using strictly intravascular contrast agents could provide a much more sensitive method for the quantification of the BBB integrity. To estimate WER, we have recently devised a powerful new method using a water exchange index (WEI) biomarker and demonstrated BBB disruption in an acute stroke model. Here, we confirm that WEI is sensitive to even very subtle changes in the integrity of the BBB caused by: (i) systemic hypercapnia and (ii) low doses of a hyperosmolar solution. In addition, we have examined the sensitivity and accuracy of WEI as a biomarker of WER using computer simulation. In particular, the dependence of the WEI-WER relation on changes in vascular blood volume, T1 relaxation of cellular magnetization and transcytolemmal water exchange was explored. Simulated WEI was found to vary linearly with WER for typically encountered exchange rate constants (1-4 Hz), regardless of the blood volume. However, for very high WER (>5 Hz), WEI became progressively more insensitive to increasing WER. The incorporation of transcytolemmal water exchange, using a three-compartment tissue model, helped to extend the linear WEI regime to slightly higher WER, but had no significant effect for most physiologically important WERs (WER < 4 Hz). Variation in cellular T1 had no effect on WEI. Using both theoretical and experimental approaches, our study validates the utility of the WEI biomarker for the monitoring of BBB integrity.

Characterization of cerebrovascular responses to hyperoxia and hypercapnia using MRI in rat.

Understanding cerebrovascular responses to hyperoxia and hypercapnia is important for investigating exogenous regulation of cerebral hemodynamics. We characterized gas-induced vascular changes in the brains of anesthetized healthy rats using magnetic resonance imaging (MRI) while the rats inhaled 100% O(2) (hyperoxia) and 5% CO(2) (hypercapnia). We used echo planar imaging (EPI), arterial spin labeling (ASL), and intravascular superparamagnetic iron oxide nanoparticles (SPION) to quantify vascular responses as measured by blood oxygenation level dependence (BOLD), cerebral blood flow (CBF), cerebral blood volume (CBV), microvascular volume (MVV), and vessel size index (VSI) in multiple brain regions. Hyperoxia resulted in a statistically significant increase in BOLD-weighted MRI signal and significant decrease in CBF and CBV (P<0.05). During hypercapnia, we observed significant increases in BOLD signal, CBF, MVV, and CBV (P<0.05). Despite the regional variability, general trends of vasoconstriction and vasodilation were reflected in VSI changes during O(2) and CO(2) challenges. Interestingly, there was an evident spatial disparity between the O(2) and CO(2) stimuli-induced functional activation maps; that is, cortical and subcortical regions of the brain exhibited notable differences in response to the two gases. Hemodynamic parameters measured in the cortical regions showed greater reactivity to CO(2), whereas these same parameters measured in subcortical regions showed greater responsivity to O(2). Our results demonstrate significant changes of hemodynamic MRI parameters during systemic hypercapnia and hyperoxia in normal cerebral tissue. These gas-dependent changes are spatiotemporally distinctive, suggesting important feasibility for exogenously controlling local cerebral perfusion.

BV-2 stimulation by lactacystin results in a strong inflammatory reaction and apoptotic neuronal death in SH-SY5Y cells.

Neuroinflammation plays a role in the pathomechanism of many neurodegenerative diseases, including Parkinson disease (PD). Proteasome inhibition has also been known to be involved in the pathology of PD. Recent studies have reported that microglial activation and dopaminergic cell death were observed in in vivo lactacystin-induced models of PD. In the present study, we investigated whether proteasome inhibition had a direct effect on the inflammatory reaction. Lactacystin treatment increased the amount of nitric oxide and tumor necrosis factor alpha (TNF-alpha) in culture media containing murine microglia (BV-2). Neuronal cell death was more pronounced when the culture media containing BV-2 cells (BV-2 conditioned media; BV-2 CM) were harvested and treated with human dopaminergic neurons (SH-SY5Y) than when treated with lactacystin alone. Apoptosis was markedly increased by treatment with BV-2 CM, which could be mitigated by pretreatment with minocycline and N(omega)-nitro-l-arginine methyl ester (L-NAME). These results suggest that proteasome inhibition can directly trigger neuroinflammation, which leads to neuronal death.

Akinetic mutism responsive to bromocriptine following subdural hematoma evacuation in a patient with hydrocephalus.

An 11-year-old girl with obstructive hydrocephalus developed akinetic mutism after treatment for hydrocephalus due to aqueductal stenosis by ventriculoperitoneal (VP) shunting. Bilateral chronic subdural hematomas developed about 2 months after insertion of the VP shunt and were evacuated. Postoperatively, the patient developed akinetic mutism, but her condition improved after administration of bromocriptine. Absence of abnormalities on dopamine transporter single photon emission computed tomography, lack of clinical response to levodopa treatment, and normal homovanillic acid concentration in the cerebrospinal fluid all indicated normal dopamine production. Pressure on the periventricular monoamine projections in the thalamus and hypothalamus without major dopamine deprivation in the striatum may have been the most important factors in the development of akinetic mutism in this patient.

Ferrous and ferric iron accumulates in the brain of aged Long-Evans Cinnamon rats, an animal model of Wilson's disease.

The Long-Evans Cinnamon (LEC) rat, which accumulates excess copper (Cu) in its liver, is an animal model of Wilson's disease. We evaluated and compared the distributions of Cu, ferrous (Fe2+), and ferric (Fe3+) iron in four-brain regions, namely, in the cerebral cortex, cerebellum, substantia nigra (SN), and striatum of LEC and Long-Evans Agouti rats at 30 and 55 weeks. Cu levels were elevated in the striatum of LEC rats, and Fe2+ and Fe3+ were higher in the striatum and SN of LEC rats. Ratios of Fe2+ to Fe3+ were > 1 in four regions, and were highest in the striatum and SN of LEC rats. Cu and iron levels were found to be augmented during aging, and we suggest that these accumulations may exert deleterious effects in aged LEC rats. This study is the first report that demonstrates regional differences of Fe2+ and Fe3+ accumulation in the brain of aged LEC rats. Further studies are required to elucidate the mechanisms of Cu and iron accumulations and of their effects.

Lesion patterns and mechanism of ischemia in internal carotid artery disease: a diffusion-weighted imaging study.

CONTEXT: Although embolism and low-flow phenomenon are the 2 main mechanisms of stroke in internal carotid artery (ICA) occlusive disease, the mechanism of border-zone infarction remains controversial. Diffusion-weighted imaging (DWI) can more easily detect small or multiple ischemic lesions than conventional imaging. OBJECTIVES: To investigate the ischemic lesion patterns on DWI and to discuss the mechanisms of stroke in ICA disease. DESIGN: Case series. SETTING: A tertiary referral center. PATIENTS: We enrolled 35 consecutive patients who had an acute ischemic stroke and (> or = 70%) stenosis or an occlusion of the extracranial ICA confirmed by cerebral angiography and an acute relevant stroke lesion on DWI within 1 week of onset, but without cardiac sources of embolism and tandem intracranial arterial disease. MAIN OUTCOME MEASURES: The lesion pattern on DWI was categorized as territorial or border zone. Multiple ischemic lesions were defined as noncontiguous lesions on DWI in more than 1 vascular territory. RESULTS: There were 3 distinctive stroke lesion patterns. (1) A territorial lesion without a border-zone lesion was found in 21 patients: superficial and superficial territorial in 9, superficial and deep territorial in 7, and single in 5. (2) A border-zone lesion with or without a territorial lesion was found in 10 patients: border zone and territorial in 9 and border zone alone in 1. (3) Bilateral hemispheric lesions were found in 4 patients. Multiple ischemic lesions were found in 29 (82.9%) of the 35 patients. No patient had episodes of hemodynamic compromise. CONCLUSIONS: An acute ischemic lesion in ICA occlusive disease is mainly multiple. Border-zone infarction was mostly associated with territorial infarction. These results support the fact that embolism is the predominant stroke mechanism in ICA occlusive disease.

Investigation of common mitochondrial point mutations in Korea.

Between 1997 and 2002, 65 patients with suspected mitochondrial diseases were screened for the mitochondrial point mutations A3243G, T3271C, A8344G, and T8356C. Among these patients, 15 were found to have one of these mutations: 12 with A3243G and 3 with A8344G. The phenotypes of A3243G and A8344G mutations were MELAS and MERRF, respectively. Many asymptomatic family members had the same mutations. In this report, detailed clinical and laboratory findings are presented.

Cerebral microbleeds in patients with hypertensive stroke. Topographical distribution in the supratentorial area.

OBJECTIVE: To analyse the topography of cerebral microbleeds (CMBs) visualized by T2*-weighted gradient-echo MR imaging in the supratentorial brain area, based on the anatomical classification of the regions and the arterial territories. BACKGROUND: CMBs are associated with hypertension and the risk of intracerebral hemorrhage; however, little is known about the cerebral topography of CMBs. METHODS: We examined 164 consecutive patients with hypertensive stroke who underwent T2*-weighted gradient-echo MRI. The anatomical locations and the vascular territories of the CMBs were determined in the subcortical white matter, basal ganglia/internal capsule and thalamus along the standard axial slices. RESULTS: We detected 2,193 CMBs in 98 patients (13.4+/-39.0 per patient). The CMBs showed a significant predilection for the temporo-occipital area of the subcortical white matter, the posterolateral part of the upper putamen, and the lateral nuclei of the mid-level thalamus. The most common arterial territories were those of the middle-posterior cerebral artery in the white matter, the middle cerebral artery in the basal ganglia, and the thalamogeniculate artery in the thalamus. CONCLUSIONS: These findings were quite similar to the cerebral topography of intracerebral hemorrhage described in the literature. Our results suggest that CMBs are regionally associated with intracerebral hemorrhage.

Topographical distribution of pontocerebellar microbleeds.

BACKGROUND AND PURPOSE: Microbleeds (MBs) visualized by use of T2*-weighted gradient-echo MR imaging are pathologic blood-breakdown products after tiny cerebral hemorrhages. The topographic distribution of the lesions has not been compared with that of symptomatic intracerebral hemorrhage (ICH). The purpose of this study was to evaluate the distribution of MBs in the pontocerebellar region and to compare it with the distribution of ICHs reported in the literature. METHODS: We examined 164 consecutive hypertensive patients with ischemic infarction or spontaneous ICH over a 1-year period. Two experienced neuroradiologists assessed cerebral localization of MBs without prior knowledge of the clinical information and in consensus. After obtaining 16 standard axial brain images, we analyzed the anatomic locations and the vascular territories of the MBs in the pontocerebellar area. RESULTS: We detected 374 pontocerebellar MBs in 40 patients (8.1 +/- 12.7). Pontine MBs showed a significant predilection for the central portion (middle part along the axial plane, 3.4 +/- 4.9 [P < .01]; medial part along the coronal plane, 3.4 +/- 4.1 [P < .01]) and mostly belonged to the territory of the anteromedial group arising from the basilar artery. Cerebellar MBs had a frequent distribution around the dentate nucleus, occurring significantly more in the lower half, in the medial part (3.4 +/- 4.6; P < .01), and in the middle part along the axial plane (4.8 +/- 7.0; P < .01). CONCLUSION: These findings were similar to the topography of ICH described in the literature. Our results suggest that MBs may be a lesional marker for ICH.

Cerebral blood volume affects blood-brain barrier integrity in an acute transient stroke model.

Insufficient vascular reserve after an ischemic stroke may induce biochemical cascades that subsequently deteriorate the blood-brain barrier (BBB) function. However, the direct relationship between poor cerebral blood volume (CBV) restoration and BBB disruption has not been examined in acute stroke. To quantify BBB integrity at acute stages of transient stroke, in particular for cases in which extravasation of the standard contrast agent (Gd-DTPA) is not observed, we adopted the water exchange index (WEI), a novel magnetic resonance image-derived parameter to estimate the water permeability across the BBB. The apparent diffusion coefficient (ADC) and R2 relaxation rate constant were also measured for outlining the tissue abnormality, while fractional CBV and WEI were quantified for assessing vascular alterations. The significantly decreased ADC and R2 in the ischemic cortices did not correlate with the changes in CBV or WEI. In contrast, a strong negative correlation between the ipsilesional WEI and CBV was found, in which stroke mice were clustered into two groups: (1) high WEI and low CBV and (2) normal WEI and CBV. The low CBV observed for mice with a disrupted BBB, characterized by a high WEI, indicates the importance of CBV restoration for maintaining BBB stability in acute stroke.

A case report of painless moving toes syndrome.

This is the first report of a case of painless moving toes syndrome with radiculopathy. The patient presented with bilateral painless moving toes and unilateral subclinical sacral (S1) radiculopathy. Bilateral movements with the unilateral lesion, and fluctuation with postural changes and distant muscle contraction suggest that the underlying pathomechanism was a central reorganization in the spinal level.