Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features.

The 'neurodegeneration with brain iron accumulation' (NBIA) disease family entails movement or cognitive impairment, often with psychiatric features. To understand how iron loading affects the brain, we studied mice with disruption of two iron regulatory genes, hemochromatosis (Hfe) and transferrin receptor 2 (Tfr2). Inductively coupled plasma atomic emission spectroscopy demonstrated increased iron in the Hfe-/- × Tfr2mut brain (P=0.002, n ≥5/group), primarily localized by Perls' staining to myelinated structures. Western immunoblotting showed increases of the iron storage protein ferritin light polypeptide and microarray and real-time reverse transcription-PCR revealed decreased transcript levels (P<0.04, n ≥5/group) for five other NBIA genes, phospholipase A2 group VI, fatty acid 2-hydroxylase, ceruloplasmin, chromosome 19 open reading frame 12 and ATPase type 13A2. Apart from the ferroxidase ceruloplasmin, all are involved in myelin homeostasis; 16 other myelin-related genes also showed reduced expression (P<0.05), although gross myelin structure and integrity appear unaffected (P>0.05). Overlap (P<0.0001) of differentially expressed genes in Hfe-/- × Tfr2mut brain with human gene co-expression networks suggests iron loading influences expression of NBIA-related and myelin-related genes co-expressed in normal human basal ganglia. There was overlap (P<0.0001) of genes differentially expressed in Hfe-/- × Tfr2mut brain and post-mortem NBIA basal ganglia. Hfe-/- × Tfr2mut mice were hyperactive (P<0.0112) without apparent cognitive impairment by IntelliCage testing (P>0.05). These results implicate myelin-related systems involved in NBIA neuropathogenesis in early responses to iron loading. This may contribute to behavioral symptoms in NBIA and hemochromatosis and is relevant to patients with abnormal iron status and psychiatric disorders involving myelin abnormalities or resistant to conventional treatments.

Ferrous iron formation following the co-aggregation of ferric iron and the Alzheimer's disease peptide ß-amyloid (1-42).

For decades, a link between increased levels of iron and areas of Alzheimer's disease (AD) pathology has been recognized, including AD lesions comprised of the peptide ß-amyloid (Aß). Despite many observations of this association, the relationship between Aß and iron is poorly understood. Using X-ray microspectroscopy, X-ray absorption spectroscopy, electron microscopy and spectrophotometric iron(II) quantification techniques, we examine the interaction between Aß(1-42) and synthetic iron(III), reminiscent of ferric iron stores in the brain. We report Aß to be capable of accumulating iron(III) within amyloid aggregates, with this process resulting in Aß-mediated reduction of iron(III) to a redox-active iron(II) phase. Additionally, we show that the presence of aluminium increases the reductive capacity of Aß, enabling the redox cycling of the iron. These results demonstrate the ability of Aß to accumulate iron, offering an explanation for previously observed local increases in iron concentration associated with AD lesions. Furthermore, the ability of iron to form redox-active iron phases from ferric precursors provides an origin both for the redox-active iron previously witnessed in AD tissue, and the increased levels of oxidative stress characteristic of AD. These interactions between Aß and iron deliver valuable insights into the process of AD progression, which may ultimately provide targets for disease therapies.

Apathy, depression, and motor symptoms have distinct and separable resting activity patterns in idiopathic Parkinson disease.

Apathy and depression are heterogeneous syndromes with symptoms that overlap clinically. This clinical overlap leads to problems with classification and diagnosis in clinical populations. No functional imaging study has attempted to separate brain regions altered in apathy from those altered in depression in a clinical population. Parkinson disease (PD) is a disorder in which apathy and depression co-exist in a single population. We evaluate the relationship between apathy, depression, and motor severity of disease in PD, focusing on the relationship between these factors and the amplitude of the low frequency fluctuation (ALFF) in the resting state. We first evaluated if the resting ALFF signal is a reliable measure for our clinical question. For this, we develop and introduce a cross validation approach we term the "Regional Mapping of Reliable Differences" (RMRD) method to evaluate reliability of regions of interest deemed "significant" by standard voxel-wise techniques. Using this approach, we show that the apathy score in this sample is best predicted by ALFF signal in the left supplementary motor cortex, the right orbitofrontal cortex, and the right middle frontal cortex, whereas depression score is best predicted by ALFF signal in the right subgenual cingulate. Disease severity was best predicted by ALFF signal in the right putamen. A number of additional regions are also statistically (but not reliably) correlated with our neuropsychological measures and disease severity. Our results support the use of resting fMRI as a means to evaluate neuropsychiatric states and motor disease progression in Parkinson disease, and the clinical and epidemiologic observation that apathy and depression are distinct pathological entities. Our finding that "significance" and "reliability" are dissociated properties of regions of interest identified as significant using standard voxel-wise techniques suggests that including reliability analyses may add useful scientific information in neurobehavioral research.

Reliability analysis of the resting state can sensitively and specifically identify the presence of Parkinson disease.

Parkinson disease (PD) is characterized by a number of motor and behavioral abnormalities that could be considered deficits of a "no task" or "resting" state, including resting motor findings and defects in emerging from a resting state (e.g., resting tremor, elevated resting tone, abulia, akinesia, apathy). PET imaging, and recently, the MRI technique of continuous arterial spin labeling (CASL) have shown evidence of changes in metabolic patterns in individuals with PD. The purpose of this study was to learn if the presence of PD could be "predicted" based on resting fluctuations of the BOLD signal. Participants were 15 healthy controls, 14 subjects with PD, and 1 subject who presented as a control but later developed PD. The amplitude of the low frequency fluctuation (ALFF) was used as an index of brain activity level in the resting state. Participants with PD using this index showed a reliable decrease in activity in a number of regions, including the supplementary motor cortex, the mesial prefrontal cortex, the right middle frontal gyrus, and the left cerebellum (lobule VII/VIII) as well as increased activity in the right cerebellum (lobule IV/V). Using a cross validation approach we term "Reliability Mapping of Regional Differences" (RMRD) to analyze our sample, we were able to reliably distinguish participants with PD from controls with 92% sensitivity and 87% specificity. Our "pre-diagnostic" subject segregated in our analysis with the PD group. These results suggest that resting fMRI should be considered for development as a biomarker and analytical tool for evaluation of PD.

Individual dopaminergic neurons show raised iron levels in Parkinson disease.

OBJECTIVE: Evidence suggests that abnormal iron metabolism is associated with Parkinson disease (PD), with raised iron levels found in pathologically affected areas in PD. It is unknown if this elevated iron is actually associated with neurons or reactive glia, and we therefore addressed this issue by determining if raised iron was present in single dopaminergic neurons. METHODS: We used unfixed frozen sections from postmortem tissue of PD patients and elderly normal individuals to avoid metal contamination and translocation. Levels of iron and other elements were measured using sensitive and specific wavelength dispersive electron probe x-ray microanalysis coupled with cathodoluminescence spectroscopy in individual substantia nigra dopaminergic neurons. RESULTS: We identified raised intraneuronal iron in single defined substantia nigra neurons in PD (mean neuronal iron 2,838 vs 1,611, p < 0.0001) but not in other movement disorders such as Huntington disease. These findings were unrelated to the density of remaining neurons. CONCLUSIONS: Primary changes in neuronal iron could lead to neurodegeneration in Parkinson disease.

In situ characterization and mapping of iron compounds in Alzheimer's disease tissue.

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 mum 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.

Methotrexate and oral ulceration.

Methotrexate is well established in the drug treatment of various neoplastic diseases. More recently it has become increasingly used as a once-weekly, low-dose treatment of disorders such as psoriasis and rheumatoid arthritis. Clinical trials have shown its effectiveness in these conditions and it is likely that dentists will encounter patients taking this drug in general dental practice. Oral ulceration can occur as a side effect of methotrexate therapy. This may be due to lack of folic acid supplementation or overdosage due to confusion regarding its once-weekly regime. Illustrations of these problems, which have initially presented in a dental setting, are given. Important drug interactions of methotrexate relevant to dentistry are discussed.

Evaluating podiatry services: testing a treatment specific measure of health status.

This study reports on the preliminary testing of a new measure designed for use alongside EQ-5D in evaluating outcomes in podiatry: the Podiatry Health Questionnaire (PHQ). Individuals aged 18 years or more, receiving podiatry services in clinic or domicilliary locations across four NHS Trusts in Yorkshire and Humberside UK took part in a questionnaire survey. Respondents reported high levels of problems on all six PHQ dimensions. Correlations suggested that the PHQ and EQ-5D were measuring distinct constructs. The levels on each dimension were well defined in terms of self-rated morbidity on the PHQ visual analogue scale (PHQvas) and the EQ-5Dvas, although PHQvas appeared to be slightly more sensitive to changes in health on the dimensions. There was a strong relationship between clinicians' Podiatry Clinical Score rating and reported symptoms for four out of six PHQ dimensions and PHQvas. The PHQ was able to distinguish respondents in terms of their self-reported morbidity in EQ-5D and in terms of their morbidity as assessed by clinicians. It is suggested that the respondent completed PHQ appears to be a useful new measure for assessing foot-related health. However, further investigation of the psychometric properties of the measure is required.

Low dose computed tomography in suspected acute renal colic.

AIM: To evaluate whether computed tomography (CT) of the renal tract in suspected renal colic using reduced exposure factors maintains diagnostic accuracy. METHODS: Prospective multi-centre cohort study. Patients with suspected renal colic were examined using computed tomography (CT) of the renal tract followed by intravenous urography (IVU) in four different centres with five different CT systems. RESULTS: Sixty-nine patients with suspected renal colic had CT of the renal tract followed by IVU. CT was performed with reduced exposure factors, giving a mean CT effective dose of 3.5 (range 2.8-4.5) mSv compared with 1.5 mSv for IVU. Ureteric calculi were detected in 43 patients: CT and IVU detected 40 (93%) ureteric calculi. CT identified other lesions causing symptoms in five patients and identified renal calculi in 24 patients. IVU identified renal calculi in six patients and made false positive diagnosis of renal calculi in seven patients. Mean examination time for CT was 5 minutes and for IVU was 80 minutes. CONCLUSION: CT examination at reduced exposure factors maintains the diagnostic accuracy recorded in other series.

Spiculation of antral margin in erosive gastritis.

Because of the low yield, conventional barium studies had been considered an unreliable methods of detecting erosions of the stomach. With the advent of the double contrast examination, the literature is now replete with examples of erosive demonstrated by this technique. As in endoscopy, the erosions are visualized "en face" only. No case, however, has been recorded in which the diagnosis was made on a profile view of the erosions. We present such a case of erosive gastritis with two unusual features in which 1) the diagnosis was made on a conventional single contrast study and 2) the lesions were identified in profile.

Separation at birth and the mother-child relationship.

Mother-child relationships were investigated between: (a) 32 mothers and their singleton children with birthweights of 2000g or less who had been separated immediately after birth for a minimum period of 17 days (index families), and (b) 32 control mothers and their singleton children, matched with index cases for type of residence, sex and month of birth, but who had not been separated at birth and whose birthweights were 2700g or greater. From interview, validated by questionnaire and semantic differential scoring, six of the index mothers, but none of the control mothers were assessed as having rejected their children. Comparisons were made between rejected and non-rejected index children. Rejection occurred more commonly in the low-birthweight group if the mother had been a teenager at the birth of her first child or of the study child, especially if she had not planned or wanted the pregnancy. The mothers of rejected children tended to have had poor relations with their own fathers, were unhappy with their life-style, and perceived their children as having difficult or unlikeable personalities. The rejected children were more likely to have had poor health, severe temper tantrums, and to cause their mothers concern over their poor appetite.

Arrangements for special and intensive care of the newborn.

All the special care baby units in three Thames health regions completed a one-day census on the number of infants in the unit, staffing, and facilities. The results were assessed in the light of the recommendations of an expert group set up by the Department of Health and Social Security. Although the provision of cots (6.1-6.9 per 1000 live births) was more generous than the estimated need and the occupancy rate (59--63%) lower than suggested, some units did not have adequate trained nursing cover at night, some did not have resident paediatricians, and some lacked essential equipment. Some small units, on the other hand, had very expensive equipment that was probably underused. Relating this provision to the regional statistics on babies needing special care showed that there was room for the rationalisation of facilities for their care. Factors that should be considered in planning such care include the size of the child-bearing population, the percentage of infants of low birth weights, and the proximity of specialist paediatric and maternity units and pathology facilities. It is also essential to monitor the effectiveness of the care by assessing the outcome in babies admitted to special units, especially those of low birth weight.