Higher blood-brain barrier permeability is associated with higher white matter hyperintensities burden.

The pathogenesis of white matter hyperintensities (WMH) is incompletely understood but blood-brain barrier (BBB) dysfunction may play a key role. This study aimed to investigate the relationship between BBB permeability and the severity of WMH burden. Consecutive participants without symptomatic stroke history presented for physical examination were recruited in this cross-sectional study and divided into three WMH burden groups according to total Fazekas scores. They received dynamic contrast-enhanced-magnetic resonance imaging to measure BBB permeability, and received Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). A total of 102 participants aged 49-90 years (mean age of 69.82 years) were enrolled (36 with low WMH burden, 35 with medium WMH burden, and 31 with high WMH burden). Multivariable linear regression analyses revealed that participants with higher WMH burden had significantly higher BBB leakage rate and area under the leakage curve in normal-appearing white matter, WMH, cortical gray matter, and deep gray matter (DGM) after adjustment for age, sex, and vascular risk factors. Scores on MMSE and MoCA decreased with increasing leakage rate in WMH and DGM after adjustment for age, sex, WMH burden, and education years. We found that higher BBB permeability is associated with higher WMH burden and cognitive decline. The compromised BBB integrity may be a critical contributor to the pathogenesis of WMH and part of a series of pathological processes that finally lead to cognitive impairment.

Assessment of metabolic fluxes in the mouse brain in vivo using 1H-[13C] NMR spectroscopy at 14.1 Tesla.

(13)C magnetic resonance spectroscopy (MRS) combined with the administration of (13)C labeled substrates uniquely allows to measure metabolic fluxes in vivo in the brain of humans and rats. The extension to mouse models may provide exclusive prospect for the investigation of models of human diseases. In the present study, the short-echo-time (TE) full-sensitivity (1)H-[(13)C] MRS sequence combined with high magnetic field (14.1 T) and infusion of [U-(13)C6] glucose was used to enhance the experimental sensitivity in vivo in the mouse brain and the (13)C turnover curves of glutamate C4, glutamine C4, glutamate+glutamine C3, aspartate C2, lactate C3, alanine C3, γ-aminobutyric acid C2, C3 and C4 were obtained. A one-compartment model was used to fit (13)C turnover curves and resulted in values of metabolic fluxes including the tricarboxylic acid (TCA) cycle flux VTCA (1.05 ± 0.04 µmol/g per minute), the exchange flux between 2-oxoglutarate and glutamate Vx (0.48 ± 0.02 µmol/g per minute), the glutamate-glutamine exchange rate V(gln) (0.20 ± 0.02 µmol/g per minute), the pyruvate dilution factor K(dil) (0.82 ± 0.01), and the ratio for the lactate conversion rate and the alanine conversion rate V(Lac)/V(Ala) (10 ± 2). This study opens the prospect of studying transgenic mouse models of brain pathologies.

A novel approach for integrative studies on neurodegenerative diseases in human brains.

Despite a massive research effort to elucidate Alzheimer's disease (AD) in recent decades, effective treatment remains elusive. This failure may relate to an oversimplification of the pathogenic processes underlying AD and also lack of understanding of AD progression during its long latent stages. Although evidence shows that the two specific neuropathological hallmarks in AD (neuronal loss and protein accumulation), which are opposite in nature, do not progress in parallel, the great majority of studies have focused on only one of these aspects. Furthermore, research focusing on single structures is likely to render an incomplete picture of AD pathogenesis because as AD involves complete brain networks, potential compensatory mechanisms within the network may ameliorate impairment of the system to a certain extent. Here, we describe an approach for enabling integrative analysis of the dual-nature lesions, simultaneously, in all components of one of the brain networks most vulnerable to AD. This approach is based on significant development of methods previously described mainly by our group that were optimized and complemented for this study. It combines unbiased stereology with immunohistochemistry and immunofluorescence, making use of advanced graphics computing for three-dimensional (3D) volume reconstructions. Although this study was performed in human brainstem and focused in AD, it may be applied to the study of any neurological disease characterized by dual-nature lesions, in humans and animal models. This approach does not require a high level of investment in new equipment and a significant number of specimens can be processed and analyzed within a funding cycle.

Radius dependence of FP-CIT quantification: a Monte Carlo-based simulation study.

OBJECTIVE: Dopamine transporter imaging with SPECT is a valuable tool for both clinical routine and research studies. Semi-quantitative analysis plays a key role in interpreting the scans, but is dependent on numerous factors, rotational radius being one of them. This study systematically evaluates the potential influence of radius of rotation on apparent tracer binding and describes methods for correction. METHODS: Monte Carlo simulation scans of a digital brain phantom with various disease states and various radii of rotation ranging from 13 to 30 cm were analyzed using 4 different methods of semi-quantification. Different volumes of interest as well as a method with partial volume correction were applied. RESULTS: For conventional 3D semi-quantification methods the decrease of measured striatal binding per cm additional radius rotation lied in the range between 2.5 and 3.1 %, whereas effects were negligible when applying recovery-corrected quantification. Effects were independent of disease state. CONCLUSION: Partial volume effects with increasing radius of rotation can lead to considerable decrease of measured binding ratios, particularly when applying dopamine transporter imaging in a research setting. Standardization of acquisition radius can avoid the effect; correction seems feasible, but the correction factors depend on the quantification approach applied.

Using MRI for the assessment of paraoxon-induced brain damage and efficacy of antidotal treatment.

Organophosphate intoxication induces neural toxicity as demonstrated in histological analysis of poisoned animals. Diffusion-weighted magnetic resonance imaging (DWMRI) enables early noninvasive characterization of biological tissues based on their water diffusion characteristics. Our objectives were to study the application of MRI for assessment of paraoxon-induced brain damage and the efficacy of antidotal treatments. Seventy-six rats were poisoned with paraoxon followed by treatment with atropine and obidoxime. The rats were then divided into five treatment groups consisting of midazolam after 1 or 30 min, scopolamine after 1 or 30 min and a no anticonvulsant treatment group. Five untreated rats served as controls. Animals underwent MRI on days 1, 8, 15, 29 and 50 post poisoning. Histological evaluation was performed on representative rat brains. Acute DWMRI effects, such as enhancement of temporal brain regions, and chronic effects such as ventricular enlargement and brain atrophy, depicted on T2-weighted MRI, were significantly more prominent in late anticonvulsant treatment groups. There was no significant difference between the neuroprotective effects of midazolam and scopolamine as shown by DWMRI. Early MRI abnormalities were found to correlate significantly with histological analysis of samples obtained 15 days post treatment. In conclusion, our results demonstrate the feasibility of using DWMRI for depiction of early cytotoxic response to paraoxon and T2-weighted MRI for later changes, thus enabling assessment of early/late brain damage as well as treatment efficacy in rats. The ability to depict these changes early and noninvasively may be applied clinically in the acute phase of organophosphate poisoning.

Brain dysmyelination and recovery assessment by noninvasive in vivo diffusion tensor magnetic resonance imaging.

Diffusion tensor magnetic resonance imaging (DT-MRI) was applied for in vivo quantification of myelin loss and regeneration. A transgenic mouse line (Oligo-TTK) expressing a truncated form of the herpes simplex virus 1 thymidine kinase gene (hsv1-tk) in oligodendrocytes was studied along with two induced phenotypes of myelin pathology. Myelin loss and axonal abnormalities differentially affect values of DT-MRI parameters in the brain of transgenic mice. Changes in the anisotropy of the white matter were assessed by calculating and mapping the radial (D perpendicular) and axial (D parallel) water diffusion to axonal tracts and fractional anisotropy (FA). A significant increase in D perpendicular attributed to the lack of myelin was observed in all selected brain white matter tracts in dysmyelinated mice. Lower D parallel values were consistent with the histological observation of axonal modifications, including reduced axonal caliber and overexpression of neurofilaments and III beta-tubulin. We show clearly that myelination and axonal changes play a role in the degree of diffusion anisotropy, because FA was significantly decreased in dysmyelinated brain. Importantly, myelin reparation during brain postnatal development induced a decrease in the magnitude of D( perpendicular) and an increase in FA compared with the same brain before recovery. The progressive increase in D parallel values was attributed to the gain in normal axonal morphology. This regeneration was confirmed by the detection of enlarged oligodendrocyte population, newly formed myelin sheaths around additional axons, and a gradual increase in axonal caliber.

NMDA receptor pathways as drug targets.

Since the mid 1980s, there has been a great deal of enthusiasm within both academia and industry about the therapeutic potential of drugs targeting the NMDA subtype of glutamate receptors. That early promise is just beginning to translate into approvable drugs. Here we review the reasons for this slow progress and critically assess the future prospects for drugs that act on NMDA receptor pathways, including potential treatments for some major disorders such as stroke and Alzheimer's disease, for which effective therapies are still lacking.

Validation of a new method for estimating resting energy expenditure of non-ambulatory tube-fed patients with severe neurodevelopmental disabilities.

OBJECTIVE: We assessed the bias and precision of the Arlington Developmental Center (ADC) equations derived from our previous study and the Harris-Benedict equations for estimating resting energy expenditure in non-ambulatory, tube-fed patients with severe neurodevelopmental disabilities. METHODS: Fifteen non-ambulatory patients with neurodevelopmental disabilities referred to the nutrition consult service for evaluation of enteral tube feeding via a permanent ostomy who had a steady-state resting energy expenditure measurement performed by indirect calorimetry were included in the study. The predicted energy expenditure values were compared with the measured resting energy expenditure values and evaluated for bias and precision. RESULTS: Both ADC equations were more precise (95% confidence interval [CI]: 9-22% and 10-18% error, respectively) for the total population than the Harris-Benedict equations (95% CI: 17-40% error). The ADC-2 equation was precise (95% CI: 7-15% error) and unbiased (95% CI: -5 to 139 kcal/d) in contrast to the Harris-Benedict equations (95% CI: 23-54% error; bias, +230 to 365 kcal/d) for patients with cerebral palsy and fixed upper extremity contractures. The Harris-Benedict equations were precise and unbiased (95% CI: 3-14% error; bias, -182 to 39 kcal/d) for patients with cerebral palsy with preservation of upper body movement, whereas the ADC equations were biased toward underprediction and associated with greater error (95% CI: -367 to -73 kcal/d and 7-26% error; 95% CI: -379 to -109 kcal/d and 9-27% error, respectively). CONCLUSIONS: The ADC-2 equation was unbiased and more precise in non-ambulatory adult patients with severe neurodevelopmental disabilities and fixed upper extremity contractures, whereas the Harris-Benedict equations were more precise and unbiased for those with preservation of limited functional and non-functional upper extremity movement.

Assessment of lesion pathology in multiple sclerosis using quantitative MRI morphometry and magnetic resonance spectroscopy.

Quantitative measurement of MRI-defined brain lesions can provide an index of the extent and activity of disease in multiple sclerosis patients. However, the relationships between these indices and clinical features are not well-understood. Heterogeneity of the pathological changes underlying MRI lesions may be an important factor determining the correlation between MRI lesion volumes and clinical measures. Recent studies have suggested that with magnetic resonance spectroscopy (MRS), it may be possible to define chemical changes that better reflect the pathological changes in multiple sclerosis. Here we report results of combined quantitative brain T2-weighted MRI lesion volume and proton MRS examinations that demonstrate heterogeneity of the chemical pathology underlying brain lesions in patients selected on the basis of similar clinical disability but differing with respect to the presence or absence of clinical relapses. We examined 29 patients with disease characterized by either clear relapses with at least partial remissions (RR) or secondary, chronic progression after an earlier history of a more relapsing and remitting course (SP). Total hemispheric lesion volume was greater (P < 0.04) in the RR (32.5 +/- 20.9 cm3) than in the SP (16.2 +/- 9.0 cm3) patients, despite the longer duration of disease in the latter group. Central brain N-acetyl aspartate: creatine (NAA:Cr) ratios were reduced relative to normal controls (4.0 +/- 0.3, n = 19) by similar amounts in the two patients groups (RR, 3.1 +/- 0.5; SP, 3.2 +/- 0.4; P < 0.0001). The ratio lesion volume:(NAA:Cr) was greater for the RR group (11.7 +/- 9.3 cm3) than for the SP group (5.4 +/- 3.3 cm3, P < 0.05), implying a greater average degree of axonal loss per unit lesion volume defined by MRI for subjects in the SP group or, alternatively, a greater proportion of lesions without axonal damage or loss in the RR group. Our results emphasize a limitation of using T2-weighted MRI lesion volume alone and suggest that combined analysis of MR-based chemical and imaging data might allow improved non-invasive assessment of lesion pathology in order to better understand its relationship to clinical features of multiple sclerosis.

[Nutritional assessment for patients with neurosurgical diseases].

There have been few guidelines in the field of nutritional management with regard to neurosurgical patients. In this review, caloric intake and nutritional parameters were measured in 24 patients in the acute stage and 32 patients in the chronic stage (prolonged unconscious state). We ascertained (1) whether the caloric intake was adequate or not, (2) the relationship between the grade of neurological damage and the nutritional assessment, and (3) we discussed the relationship between diseases and the nutritional assessments. The acute-stage patients, 14 male and 13 female, consisted of both a neurologically good prognostic group and a neurologically poor prognostic group. All of the prolonged-unconscious patients revealed poor prognosis. The nutritional assessment was referred to such parameters as, diet and nutrition, anthropometric measurements, laboratory tests, immunological parameters and prognostic nutritional index. The results were, 1) the acute stage patients received less caloric intake than their resting energy expenditure, 2) the neurologically poor prognostic patients showed muscle atrophy and decrease of creatinine-height index which represents muscle content, 3) there was no significant differences between the assessment parameters in each disease, and 4) serum electrolytes decreased in prolonged-unconscious patients with a small amount of caloric intake.

Near infrared spectroscopy. Investigation and assessment of perinatal brain injury.

Near-infrared spectroscopy is a new technique for noninvasive monitoring of tissue oxygenation and haemodynamics. Quantitative measurements can be made of oxyhaemoglobin, deoxyhaemoglobin, oxidized cytochrome and various haemodynamic indices. This technique is likely to prove increasingly valuable for: cot-side monitoring brain oxygenation and haemodynamics in babies; investigating the mechanisms of damage to the brain; according the results of treatment; and assigning long-term prognosis.

Drugs five years later: praziquantel.

PURPOSE: To identify advances in knowledge of the pharmacokinetics, mechanism of action, clinical use, and side effects of the antihelminthic drug praziquantel in the 5 years since its introduction in the United States. DATA IDENTIFICATION: Studies reported from 1983 to July 1988 were identified by computer searches of MEDLINE and TOXLINE, and review of textbooks and review articles. STUDY SELECTION: Of 57 articles originally identified, 39 were selected by two readers. DATA EXTRACTION: Study quality and significance were independently assessed by each reader. RESULTS OF DATA ANALYSIS: The pharmacokinetics and clinical efficacy of praziquantel have been well documented. Yet, despite extensive in vivo and in vitro laboratory studies, the drug's mechanism of action in killing parasites is unknown. Although the efficacy of praziquantel was first established for treating schistosomiasis, in the last 5 years its clinical use has been expanded to the treatment of intestinal, tissue, and lung flukes, and intestinal and tissue cestode infections, including neurocysticercosis. The introduction of praziquantel was a significant advance in antihelminthic therapy, in that it was effective therapy for several parasites that had been previously considered untreatable. Availability of a safe, effective broad-spectrum oral antihelminthic agent consolidated the central role of chemotherapy in population-based control of many trematode and cestode parasites. Randomized trials have shown, however, that older, cheaper agents may be more cost-effective in controlling Schistosoma mansoni and Schistosoma haematobium in some endemic areas. CONCLUSIONS: Although praziquantel is the treatment of choice for most human trematode and cestode infections, cost factors have limited its use in developing countries.

The significance of clinical assessment of brain tissue oxygenation in different pathological conditions: an overview.

The development of methods of measurement of brain oxygenation in man is reviewed and the possible clinical potential of some new and established laboratory techniques is evaluated. Advantages and problems associated with the various approaches are considered together with the difficulties that are encountered in interpretation of data obtained and the factors that may increase such difficulties. It is concluded that invasive techniques that can only be used intraoperatively are of limited value but may be helpful in confirming the edges of ischemic areas or the restoration of adequate local blood flow. Chronically implanted devices have been useful in detecting epileptic foci and in evaluation of anesthetic regimes in patients with brain lesions. Infrared spectroscopy may offer possibilities for noninvasive whole brain monitoring in patients, but the method lacks resolution.