Background and Purpose-Enlarged perivascular spaces in the brain are common but generally overlooked and of uncertain pathophysiology. They may reflect underlying cerebral small vessel disease. We determined whether enlarged perivascular spaces were associated with lacunar stroke subtype and white matter hyperintensities, markers of established small vessel disease. Materials and Methods-We prospectively recruited patients with acute ischemic lacunar or cortical stroke. Age-matched nonstroke control subjects were also recruited. We rated basal ganglia and centrum semiovale enlarged perivascular spaces 0 to 4 (0ϭnone, 4ϭϾ40) on T2-weighted MRI and white matter hyperintensities. We compared enlarged perivascular spaces between stroke subtypes and control subjects and assessed associations with vascular risk factors and white matter hyperintensities. Results-We recruited 350 patients; 129 lacunar, 124 cortical stroke, and 97 age-matched control subjects. Adjusting for vascular risk factors and white matter hyperintensities, total enlarged perivascular spaces were associated with lacunar stroke subtype (Pϭ0.04) in the acute stroke group (nϭ253); basal ganglia enlarged perivascular spaces were associated with lacunar stroke subtype (Pϭ0.003), deep (Pϭ0.02) and periventricular white matter hyperintensities (Pϭ0.01); in all 350 subjects, total enlarged perivascular spaces were associated with deep (PϽ0.001) and periventricular (PϽ0.001) white matter hyperintensities. Conclusions-Although prevalent in patients with vascular risk factors and stroke, enlarged perivascular spaces are specifically associated with lacunar ischemic stroke and white matter hyperintensities. Further studies should determine the mechanism of this association while including adequate controls to account for stroke and vascular risk factors.

Delirium is a common and serious acute neuropsychiatric syndrome with core features of inattention and cognitive impairment, and associated features including changes in arousal, altered sleep-wake cycle, and other changes in mental status. The main risk factors are old age, cognitive impairment, and other comorbidities. Though delirium has consistent core clinical features, it has a very wide range of precipitating factors, including acute illness, surgery, trauma, and drugs. The molecular mechanisms by which these precipitating factors lead to delirium are largely obscure. In this article we attempt to narrow down some specific causal pathways. We propose a basic classification for the aetiological factors: (a) direct brain insults, and (b) aberrant stress responses. Direct brain insults are largely indiscriminate and include general and regional energy deprivation (eg. hypoxia, hypoglycaemia, stroke), metabolic abnormalities (eg. hyponatraemia, hypercalcaemia), and the effects of drugs. Aberrant stress responses are conceptually and mechanistically distinct in that they constitute adverse effects of stress-response pathways which, in health, are adaptive. Ageing and central nervous system disease, two major predisposing factors for delirium, are associated with alterations in the magnitude or duration of stress and sickness behaviour responses, and increased vulnerability to the effects of these responses. We discuss in detail two stress response systems that are likely to be involved in the pathophysiology of delirium: inflammation and the sickness behaviour response, and activity of the limbichypothalamic-pituitary-adrenal axis. We conclude by discussing the implications for future research and the development of new therapies for delirium.

Objectives: Patients with type II diabetes are at increased risk of cognitive impairment. The retinal and renal complications of diabetes follow microvascular damage permitting small arterioles to leak, hence the cerebral damage might also follow loss of blood-brain barrier (BBB) integrity. Magnetic resonance (MR) brain imaging with intravenous gadolinium (Gd) diethylenetriamine pentaacetic acid (Gd-DTPA) was used to identify increased BBB permeability. Methods: Ten well controlled type II diabetic patients aged 65-70 years and 10 controls underwent MR brain imaging with fluid attenuated inversion recovery (FLAIR); T1 weighted (T1W) volumetric imaging before; and T1W volumetric imaging at 5, 15, 30, 45, 60, and 90 minutes after intravenous Gd-DTPA. The T1W image before Gd-DTPA was subtracted from the images at each time point after Gd-DTPA. Net signal intensity was plotted against time for different brain regions. White matter hyperintensities were scored from the FLAIR image. Results: The signal intensity/time curves showed that brain signal intensity increased more in the diabetic group than controls during the first 15 minutes after Gd-DTPA, particularly in the basal ganglia (p=0.018). Signal intensity in controls peaked at five minutes and diabetics at 15 minutes. Subjects with more white matter hyperintensities had greater signal increase after Gd-DTPA, whether diabetic or not (p=0.001). Conclusions: Increased BBB permeability with MR imaging was detected in patients with type II diabetes or white matter hyperintensities. Increased permeability of the BBB might account for some of the cerebral effects of type II diabetes, and so possibly also for the effect of other conditions that affect the microvasculature (like hypertension), on the brain.

Objectives: Increased white matter (WM) lesions on magnetic resonance imaging (MRI) are associated with worse cognitive function in older people. Enlarged perivascular spaces (EPVS) commonly coexist with and share some risk factors for WM lesions but are not quantified in published scales. It is not known whether the extent of EPVS is also associated with cognitive function. We tested the hypothesis that more EPVS would be associated with worse cognitive function. Methods: Ninety seven healthy men (65-70 years), not on medications, underwent MRI scanning and comprehensive cognitive testing. EPVS were quantified in both the basal ganglia/centrum semiovale and the hippocampus, and WM lesions were measured. Results: Scores on published WM lesion rating scales intercorrelated highly significantly and positively (r = 0.61 to 0.91, p,0.0001). A summary (WML) factor derived from principal components analysis of the WM scales correlated with EPVS in the basal ganglia/centrum semiovale (r = 0.48, p,0.0001) but not in the hippocampus. EPVS scores in the basal ganglia/centrum semiovale correlated significantly and negatively with non-verbal reasoning (r = 20.21, p = 0.038) and general visuospatial ability (r = 20.22, p = 0.032), adjusted for prior intelligence. The WML factor correlated significantly and negatively with visuospatial ability, as previously reported, and showed an unexpected positive correlation with one test of verbal memory (list-learning). Conclusions: These findings suggest that increased EPVS are correlated with worse cognitive function. Future studies examining changes in WM with ageing should consider incorporating measures of EPVS and examine the sequence of EPVS and WM lesion development over time. More work is needed to develop valid and reliable measures of EPVS.

ObjectiveBrain tissue segmentation by conventional threshold-based techniques may have limited accuracy and repeatability in older subjects. We present a new multispectral magnetic resonance (MR) image analysis approach for segmenting normal and abnormal brain tissue, including white matter lesions (WMLs).MethodsWe modulated two 1.5T MR sequences in the red/green colour space and calculated the tissue volumes using minimum variance quantisation. We tested it on 14 subjects, mean age 73.3 ± 10 years, representing the full range of WMLs and atrophy. We compared the results of WML segmentation with those using FLAIR-derived thresholds, examined the effect of sampling location, WML amount and field inhomogeneities, and tested observer reliability and accuracy.ResultsFLAIR-derived thresholds were significantly affected by the location used to derive the threshold (P = 0.0004) and by WML volume (P = 0.0003), and had higher intra-rater variability than the multispectral technique (mean difference ± SD: 759 ± 733 versus 69 ± 326 voxels respectively). The multispectral technique misclassified 16 times fewer WMLs.ConclusionInitial testing suggests that the multispectral technique is highly reproducible and accurate with the potential to be applied to routinely collected clinical MRI data.Electronic supplementary materialThe online version of this article (doi:10.1007/s00330-010-1718-6) contains supplementary material, which is available to authorized users.

In healthy elderly men, there are significant relationships between multiple cognitive tests and both intracranial capacity and regional brain volumes. These relationships may be largely due to longstanding associations between general cognitive ability and overall brain size.

Hyperammonemia is a universal finding after gastrointestinal hemorrhage in cirrhosis. We administered an oral amino acid solution mimicking the hemoglobin molecule to examine neuropsychological changes, brain glutamine levels, and brain magnetization transfer ratio (MTR). Forty-eight metabolically stable patients with cirrhosis and no evidence of "overt" hepatic encephalopathy (HE) were randomized to receive 75 g of amino acid solution or placebo; measurements were performed before and 4 hours after administration. Neuropsychological tests included the Trails B Test, Digit Symbol Substitution Test, memory subtest of the Randt battery, and reaction time. Plasma was collected for ammonia and amino acid measurements, and brain metabolism was studied using proton magnetic resonance (MR) spectroscopy in the first 16 randomized patients. In 7 other patients, MTR was measured. A significant increase in ammonia levels was observed in the amino acid group (amino acid group, 76 ؎ 7.3 to 121 ؎ 6.4 mol/L; placebo, 83 ؎ 3.3 to 78 ؎ 2.9 mol/L; P < .001). Neuropsychological function improved significantly in the placebo group, but no significant change in neuropsychological function was observed in the amino acid group. Brain glutamate/glutamine (Glx)/creatine (Cr) ratio increased significantly in the amino acid group. MTR decreased significantly from 30 ؎2.9 to 23 ؎ 4 (P < .01) after administration of the amino acid solution. In conclusion, an improvement in neuropsychological test results followed placebo, which was not observed in patients administered the amino acid solution. Induced hyperammonemia resulted in an increase in brain Glx/Cr ratio and a decrease in MTR, which may indicate an increase in brain water as the operative mechanism. A mmonia is believed to be central in the pathogenesis of hepatic encephalopathy (HE). [1][2][3][4] It is well known that upper gastrointestinal bleeding in cirrhotic patients produces hyperammonemia and precipitates HE. [1][2][3][4][5][6] Simulating the metabolic effects of upper gastrointestinal bleeding by oral administration of erythrocytes has been shown to induce hyperammonemia and behavioral disturbance in portacaval-shunted rats. 7 In an uncontrolled study, we showed that oral administration of an amino acid solution that is identical to the amino acid profile of hemoglobin results in deterioration in memory test results, suggesting that this may be a clinically valid model to study the pathogenesis of HE. 8 Although the data relating arterial ammonia concentration to the severity of HE are controversial, there is growing evidence that greater arterial ammonia concentrations are observed in more severe states of HE. 3,4,9 In a recent study in patients with acute liver failure, an arterial concentration of ammonia greater

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