There is a well-established link between iron overload in the brain and pathology associated with neurodegeneration in a variety of disorders such as Alzheimer's (AD), Parkinson's (PD) and Huntington's (HD) diseases [1]. This association was first discovered in AD by Goodman in 1953 [2], where, in addition to abnormally high concentrations of iron in autopsy brain tissue, iron has also been shown to accumulate at sites of brain pathology such as senile plaques [3]. However, since this discovery, progress in understanding the origin, role and nature of iron compounds associated with neurodegeneration has been slow. Here we report, for the first time, the location and characterisation of iron compounds in human AD brain tissue sections. Iron fluorescence was mapped over a frontal-lobe tissue section from an Alzheimer's patient, and anomalous iron concentrations were identified using synchrotron X-ray absorption techniques at 5 µm spatial resolution. Concentrations of ferritin and magnetite, a magnetic iron oxide potentially indicating disrupted brain-iron metabolism, were evident. These results demonstrate a practical means of correlating iron compounds and disease pathology in-situ and have clear implications for disease pathogenesis and potential therapies.

We report R2 and R2* in human hippocampus from five unfixed post-mortem Alzheimer’s disease (AD) and three age-matched control cases. Formalin-fixed tissues from opposing hemispheres in a matched AD and control were included for comparison. Imaging was performed in a 600 MHz (14T) vertical bore magnet at MR microscopy resolution to obtain R2 and R2* (62 μm × 62 μm in-plane, 80 μm slice thickness), and R1 at 250 μm isotropic resolution. R1, R2 and R2* maps were computed for individual slices in each case, and used to compare subfields between AD and controls. The magnitudes of R2 and R2* changed very little between AD and control, but their variances in the Cornu Ammonis and dentate gyrus were significantly higher in AD compared for controls (p < 0.001). To investigate the relationship between tissue iron and MRI parameters, each tissue block was cryosectioned at 30 μm in the imaging plane, and iron distribution was mapped using synchrotron microfocus X-ray fluorescence spectroscopy. A positive correlation of R2 and R2* with iron was demonstrated. While studies with fixed tissues are more straightforward to conduct, fixation can alter iron status in tissues, making measurement of unfixed tissue relevant. To our knowledge, these data represent an advance in quantitative imaging of hippocampal subfields in unfixed tissue, and the methods facilitate direct analysis of the relationship between MRI parameters and iron. The significantly increased variance in AD compared for controls warrants investigation at lower fields and in-vivo, to determine if this parameter is clinically relevant.

Several amyloidogenic proteins including insulin, β-lactoglobulin and albumin, form spherulites in vitro under non-physiological conditions. These micrometer-sized, roughly spherical structures are composed of ordered arrays of amyloid fibrils in radial arrangements which, characteristically, show a typical Maltese cross pattern of light extinction under the polarizing microscope. The physiological significance of amyloid spherulites is unknown though in Alzheimer's disease senile plaques composed primarily of β sheets of Aβ 42 have, very occasionally, been shown to give a Maltese cross pattern of light extinction under crossed polarisers. Herein we describe the first observation of the formation in vitro of spherulites of Aβ 42 . They were formed under nearphysiological conditions in which the β sheet conformation of preformed aggregates of Aβ 42 had been abolished following the addition of an excess of copper. Incubation of these preparations at 37°C for up to 9 months resulted in the formation of globular structures, 5 -20 μm in diameter, which exhibited a Maltese cross pattern of light extinction typical of spherulites. Near-identical spherulitic structures were also observed in abundance in 30 μm thick sections of Alzheimer's disease brain tissue. Synchrotron x-ray fluorescence showed that the location of these spherulites in AD tissue coincided with locally elevated concentrations of tissue copper. The formation in vitro of spherulites of Aβ 42 which morphologically appeared analogous to spherulitic structures observed in vivo strongly supports the hypothesis that spherulites and senile plaques in AD tissue are one and the same structures and that their ultimate formation may involve copper.

IntroductionDeep brain stimulation (DBS) is an effective treatment for multiple movement disorders and shows substantial promise for the treatment of some neuropsychiatric and other disorders of brain neurocircuitry. Optimal neuroanatomical lead position is a critical determinant of clinical outcomes in DBS surgery. Lead migration, defined as an unintended post-operative displacement of the DBS lead, has been previously reported. Despite several reports, however, there have been no systematic investigations of this issue. This study aimed to: 1) quantify the incidence of lead migration in a large series of DBS patients, 2) identify potential risk factors contributing to DBS lead migration, and 3) investigate the practical importance of this complication by correlating its occurrence with clinical outcomes.MethodsA database of all DBS procedures performed at UF was queried for patients who had undergone multiple post-operative DBS lead localization imaging studies separated by at least two months. Bilateral DBS implantation has commonly been performed as a staged procedure at UF, with an interval of six or more months between sides. To localize the position of each DBS lead, a head CT is acquired ~4 weeks after lead implantation and fused to the pre-operative targeting MRI. The fused targeting images (MR + stereotactic CT) acquired in preparation for the delayed second side lead implantation provide an opportunity to repeat the localization of the first implanted lead. This paradigm offers an ideal patient population for the study of delayed DBS lead migration because it provides a large cohort of patients with localization of the same implanted DBS lead at two time points. The position of the tip of each implanted DBS lead was measured on both the initial post-operative lead localization CT and the delayed CT. Lead tip displacement, intracranial lead length, and ventricular indices were collected and analyzed. Clinical outcomes were characterized with validated rating scales for all cases, and a comparison was made between outcomes of cases with lead migration versus those where migration of the lead did not occur.ResultsData from 138 leads in 132 patients with initial and delayed lead localization CT scans were analyzed. The mean distance between initial and delayed DBS lead tip position was 2.2 mm and the mean change in intracranial lead length was 0.45 mm. Significant delayed migration (>3 mm) was observed in 17 leads in 16 patients (12.3% of leads, 12.1% of patients). Factors associated with lead migration were: technical error, repetitive dystonic head movement, and twiddler’s syndrome. Outcomes were worse in dystonia patients with lead migration (p = 0.035). In the PD group, worse clinical outcomes trended in cases with lead migration.ConclusionsOver 10% of DBS leads in this large single center cohort were displaced by greater than 3 mm on delayed measurement, adversely affecting outcomes. Multiple risk factors emerged, including technical error during implantation of the DBS pulse generator and failure of ...

Three-dimensional (3D) self-assembled hierarchical bismuth oxide architectures were prepared via a solution precipitation synthesis at 85 degrees C in 45 min with the aid of polyethylene glycol-8000 (PEG-8000) as a capping agent. The morphology and crystalline phase evolution was studied versus reaction time and capping agent concentration and interpreted in terms of growth mechanisms. At higher capping agent concentrations, the as-grown 3D hierarchical flowerlike bismuth oxide was crystalline cubic gamma-phase that was previously formed only at temperature > or =640 degrees C. The morphology and crystal structure of these 3D cubic gamma-phase bismuth oxide flowers were not changed with calcining up to 600 degrees C. Photoluminescence was attributed to emission from the Bi(3+) ion by a (3)P(0),(1) --> (1)S(0) transition and from defects. The gamma-phase flowerlike bismuth oxide shows better ion conductivity than that of rodlike bismuth oxide formed without the capping agent. The flowerlike morphology was attributed to modification of the nucleation and growth kinetics by the capping agent.