Gary F. Egan

Disrupted Axonal Fiber Connectivity in Schizophrenia

BACKGROUND Schizophrenia is believed to result from abnormal functional integration of neural processes thought to arise from aberrant brain connectivity. However, evidence for anatomical dysconnectivity has been equivocal, and few studies have examined axonal fiber connectivity in schizophrenia at the level of whole-brain networks. METHODS Cortico-cortical anatomical connectivity at the scale of axonal fiber bundles was modeled as a network. Eighty-two network nodes demarcated functionally specific cortical regions. Sixty-four direction diffusion tensor-imaging coupled with whole-brain tractography was performed to map the architecture via which network nodes were interconnected in each of 74 patients with schizophrenia and 32 age- and gender-matched control subjects. Testing was performed to identify pairs of nodes between which connectivity was impaired in the patient group. The connectional architecture of patients was tested for changes in five network attributes: nodal degree, small-worldness, efficiency, path length, and clustering. RESULTS Impaired connectivity in the patient group was found to involve a distributed network of nodes comprising medial frontal, parietal/occipital, and the left temporal lobe. Although small-world attributes were conserved in schizophrenia, the cortex was interconnected more sparsely and up to 20% less efficiently in patients. Intellectual performance was found to be associated with brain efficiency in control subjects but not in patients. CONCLUSIONS This study presents evidence of widespread dysconnectivity in white-matter connectional architecture in a large sample of patients with schizophrenia. When considered from the perspective of recent evidence for impaired synaptic plasticity, this study points to a multifaceted pathophysiology in schizophrenia encompassing axonal as well as putative synaptic mechanisms.

Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export

The microtubule-associated protein tau has risk alleles for both Alzheimers disease and Parkinsons disease and mutations that cause brain degenerative diseases termed tauopathies. Aggregated tau forms neurofibrillary tangles in these pathologies, but little is certain about the function of tau or its mode of involvement in pathogenesis. Neuronal iron accumulation has been observed pathologically in the cortex in Alzheimers disease, the substantia nigra (SN) in Parkinsons disease and various brain regions in the tauopathies. Here we report that tau-knockout mice develop age-dependent brain atrophy, iron accumulation and SN neuronal loss, with concomitant cognitive deficits and parkinsonism. These changes are prevented by oral treatment with a moderate iron chelator, clioquinol. Amyloid precursor protein (APP) ferroxidase activity couples with surface ferroportin to export iron, but its activity is inhibited in Alzheimers disease, thereby causing neuronal iron accumulation. In primary neuronal culture, we found loss of tau also causes iron retention, by decreasing surface trafficking of APP. Soluble tau levels fall in affected brain regions in Alzheimers disease and tauopathies, and we found a similar decrease of soluble tau in the SN in both Parkinsons disease and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. These data suggest that the loss of soluble tau could contribute to toxic neuronal iron accumulation in Alzheimers disease, Parkinsons disease and tauopathies, and that it can be rescued pharmacologically.

An analysis of functional neuroimaging studies of dorsolateral prefrontal cortical activity in depression.

Repetitive transcranial magnetic stimulation (rTMS) is currently undergoing active investigation for use in the treatment of major depression. Recent research has indicated that current methods used to localize the site of stimulation in dorsolateral prefrontal cortex (DLPFC) are significantly inaccurate. However, little information is available on which to base a choice of stimulation site. The aim of the current study was to systematically examine imaging studies in depression to attempt to identify whether there is a pattern of imaging results that suggests an optimal site of stimulation localization. We analysed all imaging studies published prior to 2005 that examined patients with major depression. Studies reporting activation in DLPFC were identified. The DLPFC regions identified in these studies were analysed using the Talairach and Rajkowska-Goldman-Rakic coordinate systems. In addition, we conducted a quantitative meta-analysis of resting studies and studies of serotonin reuptake inhibitor antidepressant treatment. There was considerable heterogeneity in the results between studies. Changes in Brodmann area 9 were relatively consistently identified in resting, cognitive activation and treatment studies included in the meta-analysis. However, there was little consistency in the direction of these changes or the hemisphere in which they were identified. At this stage, the results of imaging studies published to date have limited capacity to inform the choice of optimal prefrontal cortical region for the use in rTMS treatment studies.

High‐resolution MRI reflects myeloarchitecture and cytoarchitecture of human cerebral cortex

Maps of cytoarchitectonically defined cortical areas have proven to be a valuable tool for anatomic localization of activated brain regions revealed by functional imaging studies. However, architectonic data require observations in a sample of postmortem brains. They can only be used reliably for comparison with functional data as probabilistic maps after spatial normalization to a common reference space. The complete architectonic analysis of an individual living brain has not been achievable to date, because the relationship remains unclear between laminar gray value changes of cerebral cortex in magnetic resonance (MR) images and those of cyto‐ and myeloarchitectonic histologic sections. We examined intensity profiles through the cortex in five imaging modalities: in vivo T1 and postmortem T2 MRI, one cell body stain, and two myelin stains. After visualizing the dissimilarities in the shapes of these profiles using a canonical analysis, differences between the profiles from the different image modalities were compared quantitatively. Subsequently, the profiles extracted from the in vivo T1‐weighted images were estimated from profiles extracted from cyto‐ and myeloarchitectonic sections using linear combinations. We could verify statistically the mixed nature of the cortical T1 signal obtained in vivo: The MR intensity profiles were significantly more similar to myeloarchitectonic than to cytoarchitectonic profiles, but a weighted sum of both fitted the T1 profiles best. Hum. Brain Mapping 24:206–215, 2005.

Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance

In addition to its role in the storage of fat, adipose tissue acts as an endocrine organ, and it contains a functional renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE) plays a key role in the RAS by converting angiotensin I to the bioactive peptide angiotensin II (Ang II). In the present study, the effect of targeting the RAS in body energy homeostasis and glucose tolerance was determined in homozygous mice in which the gene for ACE had been deleted (ACE−/−) and compared with wild-type littermates. Compared with wild-type littermates, ACE−/− mice had lower body weight and a lower proportion of body fat, especially in the abdomen. ACE−/− mice had greater fed-state total energy expenditure (TEE) and resting energy expenditure (REE) than wild-type littermates. There were pronounced increases in gene expression of enzymes related to lipolysis and fatty acid oxidation (lipoprotein lipase, carnitine palmitoyl transferase, long-chain acetyl CoA dehydrogenase) in the liver of ACE−/− mice and also lower plasma leptin. In contrast, no differences were detected in daily food intake, activity, fed-state plasma lipids, or proportion of fat excreted in fecal matter. In conclusion, the reduction in ACE activity is associated with a decreased accumulation of body fat, especially in abdominal fat depots. The decreased body fat in ACE−/− mice is independent of food intake and appears to be due to a high energy expenditure related to increased metabolism of fatty acids in the liver, with the additional effect of increased glucose tolerance.

Preterm infant hippocampal volumes correlate with later working memory deficits

Children born preterm exhibit working memory deficits. These deficits may be associated with structural brain changes observed in the neonatal period. In this study, the relationship between neonatal regional brain volumes and working memory deficits at age 2 years were investigated, with a particular interest in the dorsolateral prefrontal cortex, parietal cortex and the hippocampus. While the eligible sample consisted of 227 very preterm children who were born at the Royal Womens Hospital, Melbourne prior to 30 weeks gestation or weighing <1250 g, 156 children had complete data sets. Neonatal magnetic resonance images of the brain were obtained at term equivalent age and subsequently parcellated into eight sub-regions, while the hippocampus was manually segmented. The relationship between brain volumes for these regions and performance on a working memory task (delayed alternation) at 2 years of age was examined. Very preterm children who perseverated on the working memory task had significantly smaller hippocampal volumes than very preterm children who exhibited intact working memory, even after adjusting for relevant perinatal, sociodemographic and developmental factors. Preterm children appear to have altered hippocampal volumes by discharge from hospital which may have a lasting impact on working memory function.

In vivo identification of human cortical areas using high-resolution MRI: An approach to cerebral structure–function correlation

Understanding the relationship between the structural and functional organization of the human brain is one of the most important goals of neuroscience. Individual variability in brain structure means that it is essential to obtain this information from the same subject. To date, this has been almost impossible. Even though noninvasive functional imaging techniques such as functional MRI (fMRI) are now commonplace, there is no complementary noninvasive structural technique. We present an in vivo method of examining the detailed neuroanatomy of any individual, which can then be correlated with that individuals own functional results. This method utilizes high-resolution structural MRI to identify distinct cortical regions based on cortical lamination structure. We demonstrate that the observed MR lamination patterns relate to myeloarchitecture through a correlation of histology with MRI. In vivo high-resolution MRI studies identify striate cortex, as well as visual area V5, in four individuals, as defined by using fMRI. The anatomical identification of a cortical area (V5/MT) outside of striate cortex is a significant advance, proving it possible to identify extra-striate cortical areas and demonstrating that in vivo structural mapping of the human cerebral cortex is possible.

Magnetic resonance imaging as an approach towards identifying neuropathological biomarkers for Huntington's disease

Magnetic Resonance Imaging (MRI), functional MRI (fMRI) and Diffusion Tensor Imaging (DTI) have been central to characterisation of abnormalities in brain structure and function in both clinical and preclinical Huntingtons disease (HD). One current challenge in clinical HD research is the identification of sensitive and reliable biomarkers to detect progressive neurodegeneration and neural dysfunction, which could be used to assess the effect of therapeutic intervention on brain structure and function in a HD clinical trial. To this end, both established and novel neuroimaging approaches could potentially provide sensitive, reliable and non-invasive tools to assess long-term and dynamic effects of treatment on specific brain regions, including their microstructure and connectivity. This review examines contributions from structural MRI, fMRI and DTI studies to our current understanding of preclinical and clinical HD, and critically appraises MRI methods potentially suitable for both scientific characterisation and for use as biomarkers in HD clinical trials. A combined neuroimaging approach incorporating structural MRI, fMRI and DTI is yet to be realised in HD clinical trials, however if proven to be sensitive and reliable, these methods could potentially serve as biomarkers for use in future clinical drug trials in HD.

Identifying hypoxic tissue after acute ischemic stroke using PET and 18F-fluoromisonidazole

Objective: To show that PET with 18F-fluoromisonidazole (18F-FMISO) can detect peri-infarct hypoxic tissue in patients after ischemic stroke. Background: PET with 15O-labeled oxygen and water is the only established method for identifying the ischemic penumbra in humans. We used PET with 18F-FMISO in patients after ischemic stroke to identify hypoxic but viable peri-infarct tissue likely to represent the ischemic penumbra, and to determine how long hypoxic tissues persist after stroke. Methods: Patients with acute hemispheric ischemic stroke were studied using PET with 18F-FMISO either within 48 hours or 6 to 11 days after stroke onset. The final infarct was defined by CT performed 6 to 11 days after stroke. Tracer uptake was assessed objectively by calculating the mean activity in the contralateral (normal) hemisphere, then identifying pixels with activity greater than 3 SDs above the mean in both hemispheres. Positive studies were those with high-activity pixels ipsilateral to the infarct. Results: Fifteen patients were studied; 13 within 48 hours of stroke, 8 at 6 to 11 days, and 6 during both time periods. Hypoxic tissue was detected in 9 of the 13 patients studied within 48 hours of stroke, generally distributed in the peripheries of the infarct and adjacent peri-infarct tissues. None of the 8 patients studied 6 to 11 days after stroke exhibited increased 18F-FMISO activity. All 6 patients studied both early and late exhibited areas of increased activity during the early but not the late study. Conclusions: PET with 18F-FMISO can detect peri-infarct hypoxic tissue after acute ischemic stroke. The distribution of hypoxic tissue suggests that it may represent the ischemic penumbra. Hypoxic tissues do not persist to the subacute phase of stroke (6 to 11 days).

The fate of hypoxic tissue on 18F-fluoromisonidazole positron emission tomography after ischemic stroke.

We studied 24 patients up to 51 hours after ischemic stroke using 18F‐fluoromisonidazole positron emission tomography to determine the fate of hypoxic tissue likely to represent the ischemic penumbra. Areas of hypoxic tissue were detected on positron emission tomography in 15 patients, and computed tomography was available in 12 patients, allowing comparison with the infarct volume to determine the proportions of the hypoxic tissue volume that infarcted and survived. The proportion of patients with hypoxic tissue and the amount of hypoxic tissue detected declined with time. On average, 45% of the total hypoxic tissue volume survived and 55% infarcted. Up to 68% (mean, 17.5%) of the infarct volume was initially hypoxic. Most of the tissue “initially affected” proceeded to infarction. We correlated hypoxic tissue volumes with neurological and functional outcome assessed using the National Institutes of Health Stroke Scale, Barthel Index, and Rankin Score. Initial stroke severity correlated significantly with the “initially affected” volume, neurological deterioration during the first week after stroke with the proportion of the “initially affected” volume that infarcted, and functional outcome with the infarct volume. Significant reductions in the size of the infarct and improved clinical outcomes might be achieved if hypoxic tissue can be rescued. Ann Neurol 2000;48:228–235