Neurodegeneration in Schizophrenia: Evidence from In Vivo

Although schizophrenia is primarily considered to be a neurodevelopmental disorder, there is a growing consensus that the disorder may also involve neurodegeneration. Recent research using non-invasive neuroimaging techniques, such as magnetic resonance imaging, suggests that some patients with schizophrenia show progressive losses of gray matter in the frontal and temporal lobes of the brain. The cellular mechanisms responsible for such gray matter losses are unknown, but have been hypothesized to involve abnormal increases in apoptosis

MRI Shows More Severe Hippocampal Atrophy and Shape Deformation in Hippocampal Sclerosis Than in Alzheimer's Disease

While hippocampal atrophy is a key feature of both hippocampal sclerosis (HS) and Alzheimer's disease (AD), the pathology underlying this finding differs in these two conditions. In AD, atrophy is due primarily to loss of neurons and neuronal volume as a result of neurofibrillary tangle formation. While the etiology of HS is unknown, neuron loss in the hippocampus is severe to complete. We compared hippocampal volume and deformations from premortem MRI in 43 neuropathologically diagnosed cases of HS, AD, and normal controls (NC) selected from a longitudinal study of subcortical ischemic vascular disease (IVD Program Project). HS cases (n = 11) showed loss of neurons throughout the rostral-caudal extent of the hippocampus in one or both hemispheres. AD cases (n = 24) met NIA-Reagan criteria for high likelihood of AD. Normal control cases (n = 8) were cognitively intact and showed no significant AD or hippocampal pathology. The mean hippocampal volumes were significantly lower in HS versus AD groups (P < .001). Mean shape deformations in the CA1 and subiculum differed significantly between HS versus AD, HS versus NC, and AD versus NC (P < .0001). Additional study is needed to determine whether these differences will be meaningful for clinical diagnosis of individual cases

Open access series of imaging studies: Longitudinal MRI data in nondemented and demented older adults

The Open Access Series of Imaging Studies (OASIS) is a series of neuroimaging data sets that is publicly available for study and analysis. The present MRI data set consists of a longitudinal collection of 150 subjects aged 60 to 96 all acquired on the same scanner using identical sequences. Each subject was scanned on two or more visits, separated by at least one year for a total of 373 imaging sessions. Subjects were characterized using the Clinical Dementia Rating (CDR) as either nondemented or with very mild to mild Alzheimer‘s disease (AD). 72 of the subjects were characterized as nondemented throughout the study. 64 of the included subjects were characterized as demented at the time of their initial visits and remained so for subsequent scans, including 51 individuals with CDR 0.5 similar level of impairment to individuals elsewhere considered to have ‘mild cognitive impairment’. Another 14 subjects were characterized as nondemented at the time of their initial visit (CDR 0) and were subsequently characterized as demented at a later visit (CDR > 0). The subjects were all right-handed and include both men (n=62) and women (n=88). For each scanning session, 3 or 4 individual T1-weighted MRI scans were obtained. Multiple within-session acquisitions provide extremely high contrast-to-noise making the data amenable to a wide range of analytic approaches including automated computational analysis. Automated calculation of whole brain volume is presented to demonstrate use of the data for measuring differences associated with normal aging and AD

The effect of stress on the expression of the amyloid precursor protein in rat brain

AbstractThe abnormal processing of the amyloid precursor protein (APP) is a pivotal event in the development of the unique pathology that defines Alzheimer's disease (AD). Stress, and the associated increase in corticosteroids, appear to accelerate brain ageing and may increase vulnerability to Alzheimer's disease via altered APP processing. In this study, rats were repeatedly exposed to an unavoidable stressor, an open elevated platform. Previous studies in this laboratory have shown that a single exposure produces a marked increase in plasma corticosterone levels but animals develop tolerance to this effect between 10 and 20 daily sessions. Twenty-four hours after stress, there was an increase in the ratio of the deglycosylated form of APP in the particulate fraction of the brain, which subsequently habituated after 20 days. The levels of soluble APP (APPs) tended to be lower in the stress groups compared to controls except for a significant increase in the hippocampus after 20 days of platform exposure. Since APPs is reported to have neurotrophic properties, this increased release may represent a neuroprotective response to repeated stress. It is possible that the ability to mount this response decreases with age thus increasing the vulnerability to stress-induced AD-related pathology

Large Deformation Diffeomorphic Metric Mapping Registration of Reconstructed 3D Histological Section Images and in vivo MR Images

Our current understanding of neuroanatomical abnormalities in neuropsychiatric diseases is based largely on magnetic resonance imaging (MRI) and post mortem histological analyses of the brain. Further advances in elucidating altered brain structure in these human conditions might emerge from combining MRI and histological methods. We propose a multistage method for registering 3D volumes reconstructed from histological sections to corresponding in vivo MRI volumes from the same subjects: (1) manual segmentation of white matter (WM), gray matter (GM) and cerebrospinal fluid (CSF) compartments in histological sections, (2) alignment of consecutive histological sections using 2D rigid transformation to construct a 3D histological image volume from the aligned sections, (3) registration of reconstructed 3D histological volumes to the corresponding 3D MRI volumes using 3D affine transformation, (4) intensity normalization of images via histogram matching, and (5) registration of the volumes via intensity based large deformation diffeomorphic metric (LDDMM) image matching algorithm. Here we demonstrate the utility of our method in the transfer of cytoarchitectonic information from histological sections to identify regions of interest in MRI scans of nine adult macaque brains for morphometric analyses. LDDMM improved the accuracy of the registration via decreased distances between GM/CSF surfaces after LDDMM (0.39 ± 0.13 mm) compared to distances after affine registration (0.76 ± 0.41 mm). Similarly, WM/GM distances decreased to 0.28 ± 0.16 mm after LDDMM compared to 0.54 ± 0.39 mm after affine registration. The multistage registration method may find broad application for mapping histologically based information, for example, receptor distributions, gene expression, onto MRI volumes

The characteristics of cognitive neuroscience tests in a schizophrenia cognition clinical trial: Psychometric properties and correlations with standard measures.

In comparison to batteries of standard neuropsychological tests, cognitive neuroscience tests may offer a more specific assessment of discrete neurobiological processes that may be aberrant in schizophrenia. However, more information regarding psychometric properties and correlations with standard neuropsychological tests and functional measures is warranted to establish their validity as treatment outcome measures. The N-back and AX-Continuous Performance Task (AX-CPT) are two promising cognitive neuroscience tests designed to measure specific components of working memory and contextual processing respectively. In the current study, we report the psychometric properties of multiple outcome measures from these two tests as well as their correlations with standard neuropsychological measures and functional capacity measures. The results suggest that while the AX-CPT and N-back display favorable psychometric properties, they do not exhibit greater sensitivity or specificity with functional measures than standard neurocognitive tests

Basal Forebrain Mediated Increase in Brain CRF is Associated with Increased Cholinergic Tone and Depression

Major depression is a devastating disease that generates significant suffering and cost. After controlling for the main effects of diagnosis and Cerebrospinal Fluid Corticotropin-Releasing Factor (CSF CRF), the interaction between CSF CRF and major depression disorder diagnosis was a significant predictor of basal forebrain cholinergic nuclei volume, but not of hippocampal volume. By investigating both markers concurrently in participants with and without depression, we describe the extent to which the interaction between CSF CRF levels and depression diagnosis is associated with the volume of the forebrain cholinergic nuclei and of the hippocampus. These results contribute to our understanding of the role of brain’s stress axis in depression