Karen J. Ferguson

Increased blood–brain barrier permeability in type II diabetes demonstrated by gadolinium magnetic resonance imaging

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.

Unravelling the pathophysiology of delirium: A focus on the role of aberrant stress responses

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 etiological factors: (a) direct brain insults and (b) aberrant stress responses. Direct brain insults are largely indiscriminate and include general and regional energy deprivation (e.g., hypoxia, hypoglycaemia, stroke), metabolic abnormalities (e.g., 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 behavior 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 behavior response, and activity of the limbic-hypothalamic-pituitary-adrenal axis. We conclude by discussing the implications for future research and the development of new therapies for delirium.

Enlarged Perivascular Spaces on MRI Are a Feature of Cerebral Small Vessel Disease

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 (0=none, 4=>40) 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 (P=0.04) in the acute stroke group (n=253); basal ganglia enlarged perivascular spaces were associated with lacunar stroke subtype (P=0.003), deep (P=0.02) and periventricular white matter hyperintensities (P=0.01); in all 350 subjects, total enlarged perivascular spaces were associated with deep (P<0.001) and periventricular (P<0.001) 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. Enlarged perivascular spaces should not be overlooked in studies of small vessel disease.

Enlarged perivascular spaces are associated with cognitive function in healthy elderly men

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 (ρ = 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 (ρ = 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 (ρ = −0.21, p = 0.038) and general visuospatial ability (ρ = −0.22, 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.

Intracranial capacity and brain volumes are associated with cognition in healthy elderly men

Background Brain size and intracranial capacity are correlated with cognitive performance in young healthy adults, but data are lacking on these relationships in older healthy adults. Objective To test the hypotheses that intracranial capacity, volumes of specific brain regions, and a measure of the shared variance between brain regions are positively associated with cognitive function in a sample of healthy, unmedicated elderly men (n = 97; mean age 67.8, SD 1.3). Methods Individuals underwent MRI, with measurements of intracranial area and volumetric measurements of hippocampi, temporal lobes, and frontal lobes. Cognitive testing included measures of premorbid intelligence, fluid intelligence, verbal memory, visuospatial memory, verbal fluency, and attention and processing speed. Results Cognitive tests showed significant positive intercorrelations throughout, and regional brain volumes were also universally, significantly, and positively intercorrelated. Intracranial area and several regional brain volumes correlated with tests of premorbid and fluid intelligence and tests of visuospatial memory. Tests of verbal memory and verbal fluency did not correlate significantly with brain volumes. Structural equation modeling demonstrated that the relationships between specific cognitive tests and regional brain volumes could best be summarized by a significant positive relationship between a general brain size factor and a general cognitive factor, and not by associations between individual tests and particular brain regions. Conclusions 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.

New horizons in the pathogenesis, assessment and management of delirium

Delirium is one of the foremost unmet medical needs in healthcare. It affects one in eight hospitalised patients and is associated with multiple adverse outcomes including increased length of stay, new institutionalisation, and considerable patient distress. Recent studies also show that delirium strongly predicts future new-onset dementia, as well as accelerating existing dementia. The importance of delirium is now increasingly being recognised, with a growing research base, new professional international organisations, increased interest from policymakers, and greater prominence of delirium in educational and audit programmes. Nevertheless, the field faces several complex research and clinical challenges. In this article we focus on selected areas of recent progress and/or uncertainty in delirium research and practice. (i) Pathogenesis: recent studies in animal models using peripheral inflammatory stimuli have begun to suggest mechanisms underlying the delirium syndrome as well as its link with dementia. A growing body of blood and cerebrospinal fluid studies in humans have implicated inflammatory and stress mediators. (ii) Prevention: delirium prevention is effective in the context of research studies, but there are several unresolved issues, including what components should be included, the role of prophylactic drugs, and the overlap with general best care for hospitalised older people. (iii) Assessment: though there are several instruments for delirium screening and assessment, detection rates remain dismal. There are no clear solutions but routine screening embedded into clinical practice, and the development of new rapid screening instruments, offer potential. (iv) Management: studies are difficult given the heterogeneity of delirium and currently expert and comprehensive clinical care remains the main recommendation. Future studies may address the role of drugs for specific elements of delirium. In summary, though facing many challenges, the field continues to make progress, with several promising lines of enquiry and an expanding base of interest among researchers, clinicians and policymakers.

Choice of spectroscopic lineshape model affects metabolite peak areas and area ratios

The use of Lorentzian model lineshapes leads to systematic errors in the quantification of in vivo 1H NMR spectra. Experimental lineshapes are better modeled by the Voigt (mixed Lorentzian‐Gaussian) function, leading to more accurate fits (reduced χ2). In this work, results from a group of 41 subjects are presented. It is shown that not only are the estimated metabolite peak areas affected by the choice of lineshape model, but so too are the metabolite ratios. For example, the NAA/choline ratio was 1.92 ± 0.06 (mean ± standard error) using the Lorentzian lineshape model and 1.85 ± 0.05 using the Voigt lineshape model. The corresponding figures for NAA/creatine were 2.32 ± 0.06 and 2.10 ± 0.05 respectively, which are significantly different for the two lineshape models. An explanation of this previously unreported effect is given. This finding clearly has serious implications for the methodology and reporting of spectroscopic studies. Magn Reson Med 44:646–649, 2000.

Higher Systolic Blood Pressure Is Associated With Increased Water Diffusivity in Normal-Appearing White Matter

Background and Purpose— Hypertension is associated with the development of white matter lesions in older people. Diffusion tensor MRI can detect subtle, previsible white matter damage, but relationships between diffusion tensor MRI parameters and blood pressure (BP) remain unclear. We examined correlations among mean diffusivity (MD), fractional anisotropy and BP in 45 men aged 71 to 76 years. Methods— MD and fractional anisotropy were measured in 6 regions of interest in normal-appearing white matter. Visible white matter lesions were quantified using the Fazekas scale. Both were correlated with systolic and diastolic BP. Results— Systolic BP was positively and significantly correlated with MD in all 6 regions (r=0.31 to 0.45; P=0.037 to 0.002). MD was also correlated with diastolic BP in the genu of the corpus callosum (r=0.34, P=0.018). A summary factor derived from principal component analysis of the MD measurements accounted for 53.8% of the variance and correlated at r=0.51 (P<0.001) with systolic BP and r=0.33 (P=0.028) with diastolic BP. Fractional anisotropy did not correlate significantly with BP. Deep white matter Fazekas scores correlated with diastolic BP (&rgr;=0.35, P=0.019). Conclusions— The increase in MD without change in fractional anisotropy indicates that, in normal-appearing white matter, higher BP may be associated with increased extracellular fluid before any cytoarchitectural damage occurs.

A systematic review of brain frontal lobe parcellation techniques in magnetic resonance imaging

Manual volumetric measurement of the brain’s frontal lobe and its subregions from magnetic resonance images (MRIs) is an established method for researching neural correlates of clinical disorders or cognitive functions. However, there is no consensus between methods used to identify relevant boundaries of a given region of interest (ROI) on MRIs, and those used may bear little relation to each other or the underlying structural, functional and connective architecture. This presents challenges for the analysis and synthesis of such results. We therefore performed a systematic literature review to highlight variations in the anatomical boundaries used to measure frontal regions, contextualised by up-to-date evidence from histology, hodology and neuropsychology. We searched EMBASE and MEDLINE for studies in English reporting three-dimensional boundaries for manually delineating the brain’s frontal lobe or sub-regional ROIs from MRIs. Exclusion criteria were: exclusive use of co-ordinate grid systems; insufficient detail to allow method replication; publication in grey literature only. Papers were assessed on quality criteria relating to bias, reproducibility and protocol rationale. There was a large degree of variability in the three-dimensional boundaries of all regions used by the 208 eligible papers. Half of the reports did not justify their rationale for boundary selection, and each paper met on average only three quarters of quality criteria. For the frontal lobe and each subregion (frontal pole, anterior cingulate, dorsolateral, inferior-lateral, and orbitofrontal) we identified reproducible methods for a biologically plausible target ROI. It is hoped that this synthesis will guide the design of future volumetric studies of cerebral structure.

Delirium and Cerebrospinal Fluid S100B in Hip Fracture Patients: A Preliminary Study

OBJECTIVES Delirium is associated with an increased risk of long-term cognitive decline, suggesting the possibility of concurrent central nervous system (CNS) injury. S100B is a putative biomarker of CNS injury and elevated serum levels in delirium have been reported. Here we hypothesize that delirium is associated with raised concentrations of cerebrospinal fluid (CSF) S100B. METHODS Forty-five patients with hip fracture aged over 60 and awaiting surgery under spinal anesthesia were assessed for delirium pre- and post-operatively. CSF S100B levels were measured in samples collected at the onset of surgery. RESULTS Participants with pre-operative delirium (N = 8) had elevated Log10 CSF S100B (mean: -0.156; SD: 0.238) compared with those without delirium (mean: -0.306; SD: 0.162), Students t-test t = 2.18, df = 43, p = 0.035. CONCLUSIONS This study provides preliminary evidence of elevated CSF S100B in current delirium, consistent with findings in serum and with other studies showing elevated S100B in the presence of diverse forms of CNS injury.