Imbalances in the corticosteroid milieu have been implicated in several neuropsychiatric disorders, including depression and schizophrenia. Prefrontal cortex (PFC) dysfunction is also a hallmark of these conditions, causing impairments in executive functions such as behavioral flexibility and working memory. Recent studies have suggested that the PFC might be influenced by corticosteroids released during stress. To test this possibility, we assessed spatial working memory and behavioral flexibility in rats submitted to chronic adrenalectomy or treatment with corticosterone (25 mg/kg) or the synthetic glucocorticoid dexamethasone (300 μg/kg); the behavioral analysis was complemented by stereological evaluation of the PFC (prelimbic, infralimbic, and anterior cingulate regions), the adjacent retrosplenial and motor cortices, and the hippocampal formation. Dexamethasone treatment resulted in a pronounced impairment in working memory and behavioral flexibility, effects that correlated with neuronal loss and atrophy of layer II of the infralimbic, prelimbic, and cingulate cortices. Exposure to corticosterone produced milder impairments in behavioral flexibility, but not in working memory, and reduced the volume of layer II of all prefrontal areas. Interestingly, adrenalectomy-induced deleterious effects only became apparent on the reverse learning task and were not associated with structural alterations in the PFC. None of the experimental procedures influenced the morphology of retrosplenial or motor cortices, but stereological measurements confirmed previously observed effects of corticosteroids on hippocampal structure. Our results describe, for the first time, that imbalances in the corticosteroid environment can induce degeneration of specific layers of the PFC; these changes appear to be the morphological correlate of corticosteroid-induced impairment of PFC-dependent behavior(s).

The leukodystrophies are a clinically and pathologically heterogeneous group of white matter diseases of the central nervous system. Recent genotypic and phenotypic advances have allowed a more specific classification of the leukodystrophies but there remain many difficulties in the diagnosis.¹ Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a progressive autosomal dominant leukodystrophy with an onset typically occurring in the fourth or fifth decade of life (although with a wide spread in age at onset between 15-78 years). The clinical presentation is variable and patients have been described with dementia, seizures, parkinsonian features, spastic paraplegia, personality/behavioral changes, and dystonia.^2-4 A definitive diagnosis of HDLS has therefore relied on the characteristic pathological features being seen at brain biopsy or post mortem, ie, loss of myelin sheaths and axonal destruction, axonal spheroids, gliosis, and autofluorescent lipid-laden macrophages.^4-11 There is definite clinical overlap between HDLS and pigmentary orthochromatic leukodystrophy. The pathological hallmarks of the 2 diseases, axonal spheroids in HDLS and pigmented macrophages in pigmentary orthochromatic leukodystrophy, can be identified in both conditions and this supports HDLS and pigmentary orthochromatic leukodystrophy being referred to collectively, in a review of these 2 conditions, as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.²

We previously demonstrated that hypercorticalism induces pronounced volumetric reductions in the rat medial prefrontal cortex (mPFC) and that these structural changes correlate with deficits in executive function. By applying 3-dimensional analysis of Golgi-Cox–stained material, we now demonstrate that corticosteroids can exert differential effects on dendritic arborizations of pyramidal neurons in lamina II/III of the mPFC. Treatment with the glucocorticoid receptor–selective agonist dexamethasone and with the natural adrenosteroid, corticosterone (CORT), results in significant reductions in the total length of apical dendrites in the pyramidal neurons in lamina II/III of the anterior cingulate/prelimbic and infralimbic cortices. Interestingly, although these treatments do not affect the number of dendritic branches, they are associated with impoverished arborizations in their distal portions and, in CORT-treated animals, with increased branching in the middle portions of the apical dendritic tree. Deprivation of corticosteroids by adrenalectomy leads to decreases in total apical dendritic length and spine number, but in this case, dendritic impoverishment was restricted to the middle/proximal segments of the dendritic trees. None of the treatments influenced the architecture of the basal dendrites. These results add to our knowledge of the morphological substrates through which corticosteroids may disrupt mPFC-dependent behaviors.

We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility genes that involves converging data from several unbiased genetic and genomic tools. We tested the association between IS and genes differentially expressed between cases and controls, then determined which data mapped to previously reported linkage peaks and were nominally associated with stroke in published genome-wide association studies. We first performed gene expression profiling in peripheral blood mononuclear cells of 20 IS cases and 20 controls. Sixteen differentially expressed genes mapped to reported whole-genome linkage peaks, including the TTC7B gene, which has been associated with major cardiovascular disease. At the TTC7B locus, 46 tagging polymorphisms were tested for association in 565 Portuguese IS cases and 520 controls. Markers nominally associated in at least one test and defining associated haplotypes were then examined in 570 IS Spanish cases and 390 controls. Several polymorphisms and haplotypes in the intron 5–intron 6 region of TTC7B were also associated with IS risk in the Spanish and combined data sets. Multiple independent lines of evidence therefore support the role of TTC7B in stroke susceptibility, but further work is warranted to identify the exact risk variant and its pathogenic potential.

Cerebrovascular lesions are a frequent finding in the elderly population. However, the impact of these lesions on cognitive performance, the prevalence of vascular dementia, and the pathophysiology behind characteristic in vivo imaging findings are subject to controversy. Moreover, there are no standardised criteria for the neuropathological assessment of cerebrovascular disease or its related lesions in human post-mortem brains, and conventional histological techniques may indeed be insufficient to fully reflect the consequences of cerebrovascular disease. Here, we review and discuss both the neuropathological and in vivo imaging characteristics of cerebrovascular disease, prevalence rates of vascular dementia, and clinico-pathological correlations. We also discuss the frequent comorbidity of cerebrovascular pathology and Alzheimer’s disease pathology, as well as the difficult and controversial issue of clinically differentiating between Alzheimer’s disease, vascular dementia and mixed Alzheimer’s disease/vascular dementia. Finally, we consider additional novel approaches to complement and enhance current post-mortem assessment of cerebral human tissue. Elucidation of the pathophysiology of cerebrovascular disease, clarification of characteristic findings of in vivo imaging and knowledge about the impact of combined pathologies are needed to improve the diagnostic accuracy of clinical diagnoses.