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Background Many recent studies have identified white matter abnormalities in late life depression (LLD). These abnormalities include an increased volume of discrete white matter hyperintensities on T2-weighted imaging (WMH) and changes in the diffusion tensor properties of water. However, no study of LLD to date has examined the integrity of white matter outside of WMH (i.e., in normal-appearing white matter). Methods We performed T1- and T2-weighted imaging as well as diffusion tensor imaging (DTI) in depressed elderly subjects ( n = 73) and nondepressed control subjects ( n = 23) matched for age and cerebrovascular risk factors. The structural images were segmented into white matter, gray matter, cerebrospinal fluid, and WMH. The DTI parameters were calculated in white matter regions of interest after excluding the WMH. Results Compared with control subjects, in the LLD group there were widespread abnormalities in DTI parameters, particularly in prefrontal regions. From a comprehensive neuropsychological battery, the strongest correlations were observed between cognitive processing speed and DTI abnormalities. Conclusions These results suggest that further investigation is warranted to determine potential reversibility and/or prognosis in LLD.

Animal models with complex cortical development are useful for improving our understanding of the wide spectrum of neurodevelopmental challenges facing human preterm infants. Magnetic resonance imaging (MRI) techniques can define both cerebral injury and alterations in cerebral development with translation between animal models and the human infant. We hypothesized that the immature ferret would display a similar sequence of brain development (both grey (GM) and white matter (WM)) to that of the preterm human infant. We describe postnatal ferret neurodevelopment with conventional and diffusion MRI. The ferret is born lissencephalic with a thin cortical plate and relatively large ventricles. Cortical folding and WM maturation take place during the first month of life. From the mid-second through the third week of postnatal life, the ferret brain undergoes a similar, though less complex, pattern of maturational changes to those observed in the human brain during the second half of gestation. GM anisotropy decreases rapidly in the first three weeks of life, followed by an upward surge of surface folding and WM anisotropy over the next two weeks.

Objective: Segmented brain white matter hyperintensities were compared between subjects with late-life depression and age-matched subjects with similar vascular risk factor scores. Correlations between neuropsychological performance and whole brain-segmented white matter hyperintensities and white and gray matter volumes were also examined. Method: Eighty-three subjects with latelife depression and 32 comparison subjects underwent physical examination, psychiatric evaluation, neuropsychological testing, vascular risk factor assessment, and brain magnetic resonance imaging (MRI). Automated segmentation methods were used to compare the total brain and regional white matter hyperintensity burden between depressed patients and comparison subjects. Results: Depressed patients and comparison subjects did not differ in demographic variables, including vascular risk factor, or whole brain-segmented volumes. However, depressed subjects had seven regions of greater white matter hyperintensities located in the following white matter tracts: the superior longitudinal fasciculus, fronto-occipital fasciculus, uncinate fasciculus, extreme capsule, and inferior longitudinal fasciculus. These white matter tracts underlie brain regions associated with cognitive and emotional function. In depressed patients but not comparison subjects, volumes of three of these regions correlated with executive function; whole brain white matter hyperintensities correlated with executive function; whole brain white matter correlated with episodic memory, processing speed, and executive function; and whole brain gray matter correlated with processing speed. Conclusions: These findings support the hypothesis that the strategic location of white matter hyperintensities may be critical in late-life depression. Further, the correlation of neuropsychological deficits with the volumes of whole brain white matter hyperintensities and gray and white matter in depressed subjects but not comparison subjects supports the hypothesis of an interaction between these structural brain components and depressed status.

Background Host-species specificity of the human immunodeficiency virus (HIV) limits pathobiologic, diagnostic and therapeutic research investigations to humans and non-human primates. The emergence of humanized mice as a model for viral infection of the nervous system has overcome such restrictions enabling research for HIV-associated end organ disease including behavioral, cognitive and neuropathologic deficits reflective of neuroAIDS. Chronic HIV-1 infection of NOD/scid-IL-2Rgcnull mice transplanted with human CD34+ hematopoietic stem cells (CD34-NSG) leads to persistent viremia, profound CD4+ T lymphocyte loss and infection of human monocyte-macrophages in the meninges and perivascular spaces. Murine cells are not infected with virus. Methods Changes in mouse behavior were measured, starting at 8 weeks after viral infection. These were recorded coordinate with magnetic resonance spectroscopy metabolites including N-acetylaspartate (NAA), creatine and choline. Diffusion tensor magnetic resonance imaging (DTI) was recorded against multispectral immunohistochemical staining for neuronal markers that included microtubule associated protein-2 (MAP2), neurofilament (NF) and synaptophysin (SYN); for astrocyte glial fibrillary acidic protein (GFAP); and for microglial ionized calcium binding adaptor molecule 1 (Iba-1). Oligodendrocyte numbers and integrity were measured for myelin associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (MOG) antigens. Results Behavioral abnormalities were readily observed in HIV-1 infected mice. Longitudinal open field activity tests demonstrated lack of habituation indicating potential for memory loss and persistent anxiety in HIV-1 infected mice compared to uninfected controls. End-point NAA and creatine in the cerebral cortex increased with decreased MAG. NAA and glutamate decreased with decreased SYN and MAG. Robust inflammation reflected GFAP and Iba-1 staining intensities. DTI metrics were coordinate with deregulation of NF, Iba-1, MOG and MAG levels in the whisker barrel and MAP2, NF, MAG, MOG and SYN in the corpus callosum. Conclusions The findings are consistent with some of the clinical, biochemical and pathobiologic features of human HIV-1 nervous system infections. This model will prove useful towards investigating the mechanisms of HIV-1 induced neuropathology and in developing novel biomarkers and therapeutic strategies for disease. Electronic supplementary material The online version of this article (doi:10.1186/1750-1326-9-58) contains supplementary material, which is available to authorized users.

The HIV-1-associated neurologic disorders were described earlier in HIV-1 pandemia and are now recognized as a complex of pathologic changes related to the HIV-1 infection of brain perivascular and resident cells, such as microglia. At the same time, the significant contribution to the neurocognitive deficit in humans could be related to the secondary events, such as chronic emotional stress, chronic immune activation due to mucosal barriers deficiency, opportunistic viral and bacterial infections, malnutrition, and other factors that could not be excluded or controlled like on experimental laboratory animals. Animals carrying human hemato-lymphoid tissue and chronically infected with HIV-1 could provide valuable information about the pathogenesis of neurocognitive dysfunction and serve as a model for therapeutic development.

Neuronal damage induced by ongoing human immunodeficiency virus type 1 (HIV-1) infection was investigated in humanized NOD/scid-IL-2Rγcnullmice transplanted at birth with human CD34-positive hematopoietic stem cells. Mice infected at 5 months of age and followed for up to 15 weeks maintained significant plasma viral loads and showed reduced numbers of CD4+T-cells. Prospective serial proton magnetic resonance spectroscopy tests showed selective reductions in corticalN-acetyl aspartate in infected animals. Diffusion tensor imaging revealed structural changes in cortical gray matter. Postmortem immunofluorescence brain tissue examinations for neuronal and glial markers, captured by multispectral imaging microscopy and quantified by morphometric and fluorescence emission, showed regional reduction of neuronal soma and synaptic architectures. This was evidenced by loss of microtubule-associated protein 2, synaptophysin, and neurofilament antigens. This study is the first, to our knowledge, demonstrating lost neuronal integrity after HIV-1 infection in humanized mice. As such, the model permits studies of the relationships between ongoing viral replication and virus-associated neurodegeneration.

Metabolites are biomarkers for a broad range of central nervous system disorders serving as molecular drivers and byproducts of disease pathobiology. However, despite their importance, routine measures of brain tissue metabolomics are not readily available based on the requirements of rapid tissue preservation. They require preservation by microwave irradiation, rapid freezing or other methods designed to reduce post mortem metabolism. Our research on human immunodeficiency virus type one (HIV-1) infection has highlighted immediate needs to better link histology to neural metabolites. To this end, we investigated such needs in well-studied rodent models. First, the dynamics of brain metabolism during ex vivo tissue preparation was shown by proton magnetic resonance spectroscopy in normal mice. Second, tissue preservation methodologies were assessed using liquid chromatography tandem mass spectrometry and immunohistology to measure metabolites and neural antigens. Third, these methods were applied to two animal models. In the first, immunodeficient mice reconstituted with human peripheral blood lymphocytes then acutely infected with HIV-1. In the second, NOD scid IL2 receptor gamma chain knockout mice were humanized with CD34+ human hematopoietic stem cells and chronically infected with HIV-1. Replicate infected animals were treated with nanoformulated antiretroviral therapy (nanoART). Results from chronic infection showed that microgliosis was associated with increased myoinostitol, choline, phosphocholine concentrations and with decreased creatine concentrations. These changes were partially reversed with nanoART. Metabolite responses were contingent on the animal model. Taken together, these studies integrate brain metabolomics with histopathology towards uncovering putative biomarkers for neuroAIDS.

SummarySpatial neglect is a syndrome following stroke manifesting attentional deficits in perceiving and responding to stimuli in the contralesional field. We examined brain network integrity in patients with neglect by measuring coherent fluctuations of fMRI signals (functional connectivity). Connectivity in two largely separate attention networks located in dorsal and ventral frontoparietal areas was assessed at both acute and chronic stages of recovery. Connectivity in the ventral network, part of which directly lesioned, was diffusely disrupted and showed no recovery. In the structurally intact dorsal network, interhemispheric connectivity in posterior parietal cortex was acutely disrupted but fully recovered. This acute disruption, and disrupted connectivity in specific pathways in the ventral network, strongly correlated with impaired attentional processing across subjects. Lastly, disconnection of the white matter tracts connecting frontal and parietal cortices was associated with more severe neglect and more disrupted functional connectivity. These findings support a network view in understanding neglect.