Paranasal sinus occupancy assessed from magnetic resonance images-associations with clinical indicators in patients with systemic lupus erythematosus.

OBJECTIVES: Nasal, paranasal sinus and mucosal disorders are common symptoms in autoimmune rheumatic diseases. Soft tissue changes and fluid accumulation in the osteomeatal complexes and paranasal sinuses manifest as opaqueness on radiological images which can be assessed using visual scoring and computational methods on CT scans, but their results do not always correlate. Using MRI, we investigate the applicability of different image analysis methods in SLE. METHODS: We assessed paranasal sinus opaqueness on MRI from 51 SLE patients, using three visual scoring systems and expert-delineated computational volumes, and examined their association with markers of disease activity, inflammation, endothelial dysfunction and common small vessel disease (SVD) indicators, adjusting for age and sex-at-birth. RESULTS: The average paranasal sinus volume occupation was 4.55 (6.47%) [median (interquartile range) = 0.67 (0.25-2.65) ml], mainly in the maxillary and ethmoid sinuses. It was highly correlated with Lund-Mackay (LM) scores modified at 50% opaqueness cut-off (Spearman's ρ: 0.71 maxillary and 0.618 ethmoids, P < 0.001 in all), and with more granular variations of the LM system. The modified LM scores were associated with SVD scores (0: B = 5.078, s.e. = 1.69, P = 0.0026; 2: B = -0.066, s.e. = 0.023, P = 0.0045) and disease activity (anti-dsDNA: B = 4.59, s.e. = 2.22, P = 0.045; SLEDAI 3-7: 2.86 < B < 4.30; 1.38 < s.e. < 1.63; 0.0083 ≤ P ≤ 0.0375). Computationally derived percent opaqueness yielded similar results. CONCLUSION: In patients with SLE, MRI computational assessment of sinuses opaqueness and LM scores modified at a 50% cut-off may be useful tools in understanding the relationships among paranasal sinus occupancy, disease activity and SVD markers.

A systematic review of neuroimaging in delirium: predictors, correlates and consequences.

OBJECTIVE: Neuroimaging advances our understanding of delirium pathophysiology and its consequences. A previous systematic review identified 12 studies (total participants N = 764, delirium cases N = 194; years 1989-2007) and found associations with white matter hyperintensities (WMH) and cerebral atrophy. Our objectives were to perform an updated systematic review of neuroimaging studies in delirium published since January 2006 and summarise the available literature on predictors, correlates or outcomes. METHODS: Studies were identified by keyword and MeSH-based electronic searches of EMBASE, MEDLINE and PsycINFO combining terms for neuroimaging, brain structure and delirium. We included neuroimaging studies of delirium in adults using validated delirium assessment methods. RESULTS: Thirty-two studies (total N = 3187, delirium N = 1086) met the inclusion criteria. Imaging included magnetic resonance imaging (MRI; N = 9), computed tomography (N = 4), diffusion tensor imaging (N = 3), transcranial Doppler (N = 5), near infrared spectroscopy (N = 5), functional-MRI (N = 2), single photon emission computed tomography (N = 1), proton MRI spectroscopy (N = 1), arterial spin-labelling MRI (N = 1) and 2-13 fluoro-2-deoxyglucose positron emission tomography (N = 1). Despite heterogeneity in study design, delirium was associated with WMH, lower brain volume, atrophy, dysconnectivity, impaired cerebral autoregulation, reduced blood flow and cerebral oxygenation and glucose hypometabolism. There was evidence of long-term brain changes following intensive care unit delirium. CONCLUSIONS: Neuroimaging is now used more widely in delirium research due to advances in technology. However, imaging delirious patients presents challenges leading to methodological limitations and restricted generalisability. The findings that atrophy and WMH burden predict delirium replicates findings from the original review, while advanced techniques have identified other substrates and mechanisms that warrant further investigation.

Corrigendum to Correlational structure of 'frontal' tests and intelligence tests indicates two components with asymmetrical neurostructural correlates in old age Intelligence 46 (2014) 94-106.

[This corrects the article DOI: 10.1016/j.intell.2014.05.006.].

Visual Rating Scales of White Matter Hyperintensities and Atrophy: Comparison of Computed Tomography and Magnetic Resonance Imaging.

GOAL: Magnetic resonance imaging (MRI) is the preferred modality for research on structural age-related brain changes. However, computed tomography (CT) is widely available and has practical and cost advantages over MRI for large-scale brain imaging research studies in acutely unwell patients. However, the relationships between MRI and CT measures of white matter hyperintensities (WMH) and atrophy are unclear. We examined the relationships between visual ratings of WMH, atrophy, and old infarcts in patients who had both CT and MRI scans. MATERIALS AND METHODS: Patients who had both CT and MRI scans in the International Stroke Trial-3 were studied. In both modalities, 2 raters independently completed standardized visual rating scales for WMH, and for central and superficial atrophy using a 5-point scale. In addition, 1 rater recorded old infarcts according to size and location. FINDINGS: Seventy patients with a mean age of 69 years were studied. There were moderate to substantial intrarater CT-MRI agreements for periventricular components of WMH scales (weighted Κappa = .55-.75). Agreements for basal ganglia ratings were lower (weighted Κappa = .18-.44), partly because of the misclassification of prominent perivascular spaces. Atrophy scales showed moderate to substantial CT-MRI agreements (weighted Κappa = .44-.70). MRI was more sensitive in the detection of smaller infarcts and cavitated lesions. CONCLUSIONS: Standardized visual rating scales of white matter lesions and atrophy mostly show substantial agreement between CT and MRI. Clinical CT scans have a strong potential for wider exploitation in research studies, particularly in acutely unwell populations.

Volumetric and Correlational Implications of Brain Parcellation Method Selection: A 3-Way Comparison in the Frontal Lobes.

OBJECTIVE: The aims of this study were to compare distinct brain frontal lobe parcellation methods across 90 brain magnetic resonance imaging scans and examine their associations with cognition in older age. METHODS: Three parcellation methods (Manual, FreeSurfer, and Stereology) were applied to T1-weighted magnetic resonance imaging of 90 older men, aged ∼ 73 years. A measure of general fluid intelligence (gf) associated with dorsolateral frontal regions was also derived from a contemporaneous psychological test battery. RESULTS: Despite highly discordant raw volumes for the same nominal regions, Manual and FreeSurfer (but not Stereology) left dorsolateral measures were significantly correlated with gf (r > 0.22), whereas orbital and inferior lateral volumes were not, consistent with the hypothesized frontal localization of gf. CONCLUSIONS: Individual differences in specific frontal lobe brain volumes--variously measured--show consistent associations with cognitive ability in older age. Importantly, differences in parcellation protocol for some regions that may impact the outcome of brain-cognition analyses are discussed.

Correlational structure of 'frontal' tests and intelligence tests indicates two components with asymmetrical neurostructural correlates in old age.

Both general fluid intelligence (gf) and performance on some 'frontal tests' of cognition decline with age. Both types of ability are at least partially dependent on the integrity of the frontal lobes, which also deteriorate with age. Overlap between these two methods of assessing complex cognition in older age remains unclear. Such overlap could be investigated using inter-test correlations alone, as in previous studies, but this would be enhanced by ascertaining whether frontal test performance and gf share neurobiological variance. To this end, we examined relationships between gf and 6 frontal tests (Tower, Self-Ordered Pointing, Simon, Moral Dilemmas, Reversal Learning and Faux Pas tests) in 90 healthy males, aged ~ 73 years. We interpreted their correlational structure using principal component analysis, and in relation to MRI-derived regional frontal lobe volumes (relative to maximal healthy brain size). gf correlated significantly and positively (.24 ≤ r ≤ .53) with the majority of frontal test scores. Some frontal test scores also exhibited shared variance after controlling for gf. Principal component analysis of test scores identified units of gf-common and gf-independent variance. The former was associated with variance in the left dorsolateral (DL) and anterior cingulate (AC) regions, and the latter with variance in the right DL and AC regions. Thus, we identify two biologically-meaningful components of variance in complex cognitive performance in older age and suggest that age-related changes to DL and AC have the greatest cognitive impact.

Cerebellar vermis size and cognitive ability in community-dwelling elderly men.

The cerebellum participates in multiple cognitive functions, including those that are sensitive to decline with aging, and is also vulnerable to atrophy with aging. However, few studies have examined structure-function relationships in older adults. We measured the cross-sectional area of four areas of the cerebellar vermis in 45 community-dwelling men aged 71-76, and correlated this with individual cognitive test scores and two cognitive factors derived from principal components analysis. Two out of the four areas showed positive correlations; vermis area 4 (lobules VIII-X) correlated at r = 0.47 (p = 0.001) with a general cognitive factor accounting for almost half of the cognitive test variance. These findings support the hypothesis that variations in cerebellar structure are associated with cognitive ability in older adults.

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), Student's 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.

New horizons in the pathogenesis, assessment and management of delirium.

UNLABELLED: 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.

Assessing the performance of atlas-based prefrontal brain parcellation in an aging cohort.

OBJECTIVE: It is unclear whether atlas-based parcellation is suitable in aging cohorts because age-related brain changes confound the performance of automatic methods. We assessed atlas-based parcellation of the prefrontal lobe in an aging population using visual assessment and volumetric and spatial concordance. METHODS: We used an atlas-based approach to parcellate brain MR images of 90 non-demented healthy adults, aged 72.7 ± 0.7 years, and assessed performance. RESULTS: Volumetric assessment showed that both single-atlas- and multi-atlas-based methods performed acceptably (intraclass correlation coefficient [ICC], 0.74-0.76). Spatial overlap measurements showed that multi-atlas (dice coefficient [DC], 0.84) offered an improvement over the single-atlas (DC, 0.75-0.78) approach. Visual assessment also showed that multi-atlas outperformed single atlas and identified an additional postprocessing step of cerebrospinal fluid removal, enhancing concordance (intraclass correlation coefficient, 0.86; DC, 0.89). CONCLUSIONS: Atlas-based parcellation performed reasonably well in the aging population. Rigorous performance assessment aided method refinement and emphasizes the importance of age matching and postprocessing. Further work is required in more varied subjects.

Neck muscle cross-sectional area, brain volume and cognition in healthy older men: a cohort study.

BACKGROUND: Two important consequences of the normal ageing process are sarcopenia (the age-related loss of muscle mass and function) and age-related cognitive decline. Existing data support positive relationships between muscle function, cognition and brain structure. However, studies investigating these relationships at older ages are lacking and rarely include a measure of muscle size. Here we test whether neck muscle size is positively associated with cognition and brain structure in older men. METHODS: We studied 51 healthy older men with mean age 73.8 (sd 1.5) years. Neck muscle cross-sectional area (CSA) was measured from T1-weighted MR-brain scans using a validated technique. We measured multiple cognitive domains including verbal and visuospatial memory, executive functioning and estimated prior cognitive ability. Whole brain, ventricular, hippocampal and cerebellar volumes were measured with MRI. General linear models (ANCOVA) were performed. RESULTS: Larger neck muscle CSA was associated with less whole brain atrophy (t = 2.86, p = 0.01, partial eta squared 17%). Neck muscle CSA was not associated with other neuroimaging variables or current cognitive ability. Smaller neck muscle CSA was unexpectedly associated with higher prior cognition (t = -2.12, p < 0.05, partial eta squared 10%). CONCLUSIONS: In healthy older men, preservation of whole brain volume (i.e. less atrophy) is associated with larger muscle size. Longitudinal ageing studies are now required to investigate these relationships further.

Paranasal sinuses opacification on magnetic resonance imaging in relation to brain health in sporadic small vessel disease - Systematic review and pilot analysis.

BACKGROUND: The paranasal sinus mucosal thickening, visible in magnetic resonance imaging (MRI), maybe a source of inflammation in microvessels, but its relationship with small vessel disease (SVD) is unclear. We reviewed the literature and analysed a sample of patients with sporadic SVD to identify any association between paranasal sinus opacification severity and SVD neuroimaging markers. METHODS: We systematically reviewed MEDLINE and EMBASE databases up to April 2020 for studies on paranasal sinus mucosal changes in patients with SVD, cerebrovascular disease (CVD), and age-related neurodegenerative diseases. We analysed clinical and MRI data from 100 participants in a prospective study, the Mild Stroke Study 3 (ISRCTN 12113543) at 1-3, 6 and 12 months following a minor stroke to test key outcomes from the literature review. We used multivariate linear regression to explore associations between modified Lund-Mackay (LM) scores and brain, white matter hyperintensities (WMH), enlarged perivascular spaces (PVS) volumes at each time point, adjusted for baseline age, sex, diabetes, hypercholesterolaemia, hypertension and smoking. RESULTS: The literature review, after screening 3652 publications, yielded 11 primary studies, for qualitative synthesis with contradictory results, as positive associations/higher risk from 5/7 CVD studies were contradicted by the two studies with largest samples, and data from dementia studies was equally split in their outcome. From the pilot sample of patients analysed (female N = 33, mean age 67.42 (9.70) years), total LM scores had a borderline negative association with PVS in the centrum semiovale at baseline and 6 months (B = -0.25, SE = 0.14, p = 0.06) but were not associated with average brain tissue, WMH or normal-appearing white matter volumes. CONCLUSION: The inconclusive results from the literature review and empirical study justify larger studies between PVS volume and paranasal sinuses opacification in patients with sporadic SVD.

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.

Quantifying the effects of normal ageing on white matter structure using unsupervised tract shape modelling.

Quantitative tractography may provide insights into regional heterogeneity of changes in white matter structure in normal ageing. Here we examine how brain atrophy and white matter lesions affect correlations between tract shape, tract integrity and age in a range of frontal and non-frontal tracts in 90 non-demented subjects aged over 65 years using an enhanced version of probabilistic neighbourhood tractography. This novel method for automatic single seed point placement employs unsupervised learning and streamline selection to provide reliable and accurate tract segmentation, whilst also indicating how the shape of an individual tract compares to that of a predefined reference tract. There were significant negative correlations between tract shape similarity to reference tracts derived from a young brain white matter atlas and age in genu and splenium of corpus callosum. Controlling for intracranial and lateral ventricle volume, the latter of which increased significantly with age, attenuated these correlations by 40% and 84%, respectively, indicating that this age-related change in callosal tract topology is significantly mediated by global atrophy and ventricular enlargement. In accordance with the "frontal ageing" hypothesis, there was a significant positive correlation between mean diffusivity (D) and age, and a significant negative correlation between fractional anisotropy (FA) and age in corpus callosum genu; correlations not seen in splenium. Significant positive correlations were also observed between D and age in bilateral cingulum cingulate gyri, uncinate fasciculi and right corticospinal tract. This pattern of correlations was not, however, reproduced when those subjects with significant white matter lesion load were analyzed separately from those without. These data therefore suggest that brain atrophy and white matter lesions play a significant role in driving regional patterns of age-related changes in white matter tract shape and integrity.

New multispectral MRI data fusion technique for white matter lesion segmentation: method and comparison with thresholding in FLAIR images.

OBJECTIVE: Brain 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). METHODS: We 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. RESULTS: FLAIR-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. CONCLUSION: Initial testing suggests that the multispectral technique is highly reproducible and accurate with the potential to be applied to routinely collected clinical MRI data.

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 (rho=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.

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.

Associations between hippocampal morphology, diffusion characteristics, and salivary cortisol in older men.

High, unabated glucocorticoid (GC) levels are thought to selectively damage certain tissue types. The hippocampus is thought to be particularly susceptible to such effects, and though findings from animal models and human patients provide some support for this hypothesis, evidence for associations between elevated GCs and lower hippocampal volumes in older age (when GC levels are at greater risk of dysregulation) is inconclusive. To address the possibility that the effects of GCs in non-pathological ageing may be too subtle for gross volumetry to reliably detect, we analyse associations between salivary cortisol (diurnal and reactive measures), hippocampal morphology and diffusion characteristics in 88 males, aged ∼73 years. However, our results provide only weak support for this hypothesis. Though nominally significant peaks in morphology were found in both hippocampi across all salivary cortisol measures (standardised ß magnitudes<0.518, puncorrected>0.0000003), associations were both positive and negative, and none survived false discovery rate correction. We found one single significant association (out of 12 comparisons) between a general measure of hippocampal diffusion and reactive cortisol slope (ß=0.290, p=0.008) which appeared to be driven predominantly by mean diffusivity but did not survive correction for multiple testing. The current data therefore do not clearly support the hypothesis that elevated cortisol levels are associated with subtle variations in hippocampal shape or microstructure in non-pathological older age.

Smaller left anterior cingulate cortex volumes are associated with impaired hypothalamic-pituitary-adrenal axis regulation in healthy elderly men.

CONTEXT: Studies in animals suggest that the limbic prefrontal cortex, including the anterior cingulate cortex, is involved in regulation of the hypothalamic-pituitary-adrenal (HPA) axis, but human data are lacking. OBJECTIVE: This study tested the hypothesis that smaller anterior cingulate cortex volumes are associated with HPA axis dysregulation in healthy older men. DESIGN AND PARTICIPANTS: Comparison was made of volumes of bilateral anterior cingulate cortex, hippocampus, and superior frontal gyrus (control region) volumes in two groups of 10 healthy men, aged 65-70 yr, who showed nonsuppression or suppression of cortisol levels in response to low dose (250 microg) dexamethasone. Analysis of brain volumes was performed blind to the cortisol levels. SETTING: This study was performed at a tertiary care clinical research center. RESULTS: Nonsuppressors had significantly smaller left anterior cingulate cortex volumes than suppressors (5757 vs. 7817 mm(3); P = 0.01). Right anterior cingulate cortex, bilateral hippocampus, and bilateral superior frontal gyrus volumes were not significantly different between nonsuppressors and suppressors. CONCLUSIONS: Smaller left anterior cingulate cortex volumes may be associated with HPA axis dysregulation in humans. These results substantiate evidence from animal studies indicating an important role for the anterior cingulate cortex in suprahypothalamic feedback regulation of the HPA axis. The results also have implications for disorders in which HPA axis dysregulation and abnormalities of the anterior cingulate cortex are frequently observed, such as depression and Alzheimer's disease.

Plasma cortisol levels, brain volumes and cognition in healthy elderly men.

PURPOSE: In ageing animals, exposure to chronic high levels of glucocorticoids is associated with cognitive impairment and hippocampal atrophy. However, there are few studies examining relationships among glucocorticoids, brain volumes and cognitive function in healthy older humans. This study examined the hypotheses that higher plasma cortisol levels and altered sensitivity to glucocorticoids are associated with worse cognition and more brain atrophy in elderly men. MATERIALS AND METHODS: Ninety-seven healthy men aged 65-70 had plasma cortisol measured at 09:00, 14:30 h, and post-dexamethasone (0.25mg, 09:00 h), and had dermal sensitivity to glucocorticoids measured. They also underwent cognitive testing, with scores adjusted for estimated prior mental ability, and had MRI measurements of intracranial area (a validated estimate of intracranial capacity), and hippocampus, temporal lobe and frontal lobe volumes. RESULTS: Plasma cortisol levels at 09:00 h were significantly and negatively correlated with a summary General Cognitive Factor accounting for 51% of the variance of cognitive function (rho=-0.22, p=0.035), and specific cognitive tests: delayed paragraph recall (rho=-0.28, p=0.036) and processing speed (rho=-0.23, p=0.026). Regional brain volumes adjusted for intracranial area generally did not correlate with cortisol levels. Tissue glucocorticoid sensitivity did not correlate with any measure of cognition or brain volume. CONCLUSIONS: In healthy older men, higher plasma cortisol levels are associated with worse ageing-related overall cognitive change but not ageing-related brain atrophy.