Iron overload accelerates neuronal amyloid-ß production and cognitive impairment in transgenic mice model of Alzheimer's disease.

Iron dyshomeostasis is proving increasingly likely to be involved in the pathology of Alzheimer's disease (AD); yet, its mechanism is not well understood. Here, we investigated the AD-related mechanism(s) of iron-sulfate exposure in vitro and in vivo, using cultured primary cortical neurons and APP/PS1 AD-model mice, respectively. In both systems, we observed iron-induced disruptions of amyloid precursor protein (APP) processing, neuronal signaling, and cognitive behavior. Iron overload increased production of amyloidogenic KPI-APP and amyloid beta. Further, this APP misprocessing was blocked by MK-801 in vitro, suggesting the effect was N-methyl-D-aspartate receptor (NMDAR) dependent. Calcium imaging confirmed that 24 hours iron exposure led to disrupted synaptic signaling by augmenting GluN2B-containing NMDAR expression-GluN2B messenger RNA and protein levels were increased and promoting excessing extrasynaptic NMDAR signaling. The disrupted GluN2B expression was concurrent with diminished expression of the splicing factors, sc35 and hnRNPA1. In APP/PS1 mice, chronic iron treatment led to hastened progression of cognitive impairment with the novel object recognition discrimination index, revealing a deficit at the age of 4 months, concomitant with augmented GluN2B expression. Together, these data suggest iron-induced APP misprocessing and hastened cognitive decline occur through inordinate extrasynaptic NMDAR activation.

Challenges of adherence and persistence with iron chelation therapy.

Due to advances in medical sciences, many chronic diseases that formerly resulted in early death can now be effectively managed with long-term treatment regimens. Patients with potentially fatal anemias, for example, can be treated with ongoing blood transfusions and iron chelation therapy. Ensuring adherence and persistence is challenging, as the benefits of therapy are not perceived immediately. Poor adherence severely compromises the effectiveness of treatment and, therefore, improving compliance in terms of quality of life and health economics is critical. Although adherence to chelation therapy is generally poor, the availability of oral iron chelators may help to improve patient compliance. For chronic conditions such as thalassemia major, even when oral chelation therapy is available, support by an integrated team including a clinical psychologist and nurse specialist working with the treatment center is recommended to achieve optimal results.

An instrument assessing satisfaction with iron chelation therapy: Psychometric testing from an open-label clinical trial.

INTRODUCTION: The Satisfaction with Iron Chelation Therapy (SICT) instrument was developed based on a literature review, in-depth patient and clinician interviews, and cognitive debriefing interviews. An, open-label, single arm, multicenter trial evaluating the efficacy and safety of deferasirox in patients diagnosed with transfusion-dependent iron overload, provided an opportunity to assess the psychometric measurement properties of the instrument. METHODS: Psychometric analyses were performed using data at baseline from 273 patients with a range of transfusion-dependent iron overload conditions who were participating in a multinational study. Responsiveness was further evaluated for all patients who also had subsequent satisfaction domain scores collected at week 4. RESULTS: Baseline SICT domain scores had acceptable floor and ceiling effects and internal consistency reliability (Cronbach's alpha: 0.75-0.85). Item discriminant and item convergent validity were both excellent although one item in each analysis did not meet the specified criterion. Small to moderate correlations were observed between SICT and Short Form 36 Health Survey (SF-36) domain scores. Patients with the highest levels of serum ferritin at baseline (>3100 ng/mL) were the least satisfied about the Perceived Effectiveness of ICT and vice versa. Satisfaction improved in all patients, although there were no clear differences observed between groups of patients defined according to changes in serum ferritin levels from baseline to week 4 (stable, improved, or worsened). CONCLUSIONS: The SICT domains are reliable and valid. Further testing using a more specific criterion (such as assessing patient global ratings of change in satisfaction domains that correspond to the SICT domains) could help to establish with greater confidence the responsiveness of the instrument.

Socio-psychological impact of infused iron chelation therapy with deferoxamine in metropolitan France: ISOSFER study results.

Deferoxamine (DFO) is an iron chelator used to treat iron overload in patients receiving chronic blood transfusions, and is usually administered as overnight subcutaneous infusions. ISOSFER was a prospective, observational, cross-sectional study conducted in metropolitan France that evaluated patient characteristics, quality of life (QoL), compliance and patient satisfaction with DFO monotherapy. Of 70 patients with either thalassemia, sickle cell disease or myelodysplastic syndromes, 30% were 'satisfied' or 'very satisfied' with DFO. Patients' SF-36 scores were lower than those of the general French population, and lower among patients with comorbidities and those dissatisfied with treatment. Although 72% of patients had good compliance to DFO, 57% reported missing at least one infusion in the previous month, and 82% of patients expressed a preference for oral therapy. These results suggest that QoL is severely compromised in patients receiving DFO, and that compliance is not optimal.

Functional consequences of iron overload in catecholaminergic interactions: the Youdim factor.

The influence of postnatal iron overload upon implications of the functional and interactive role of dopaminergic and noradrenergic pathways that contribute to the expressions of movement disorder and psychotic behaviours in mice was studied in a series of experiments. (1) Postnatal iron overload at doses of 7.5 mg/kg (administered on Days 10-12 post partum) and above, invariably induced a behavioural syndrome consisting of an initial (1st 20-40 min of a 60-min test session) hypoactivity followed by a later (final 20 min of a 60-min test session) hyperactivity, when the mice were tested at adult ages (age 60 days or more). (2) Following postnatal iron overload, subchronic treatment with the neuroleptic compounds, clozapine and haloperidol, dose-dependently reversed the initial hypoactivity and later hyperactivity induced by the metal. Furthermore, DA D(2) receptor supersensitivity (as assessed using the apomorphine-induced behaviour test) was directly and positively correlated with iron concentrations in the basal ganglia. (3) Brain noradrenaline (NA) denervation, using the selective NA neurotoxin, DSP4, prior to administration of the selective DA neurotoxin, MPTP, exacerbated both the functional (hypokinesia) and neurochemical (DA depletion) effects of the latter neurotoxin. Treatment with L-Dopa restored motor activity only in the animals that had not undergone NA denervation. These findings suggest an essential neonatal iron overload, termed "the Youdim factor", directing a DA-NA interactive component in co-morbid disorders of nigrostriatal-limbic brain regions.

The impact of iron overload and its treatment on quality of life: results from a literature review.

BACKGROUND: To assess the literature for the impact of iron overload and infusion Iron Chelation Therapy (ICT) on patients' quality of life (QoL), and the availability of QoL instruments for patients undergoing infusion ICT. Also, to obtain patients' experiences of having iron overload and receiving infusion ICT, and experts' clinical opinions about the impact of treatment on patients' lives. METHODS: A search of studies published between 1966 and 2004 was conducted using Medline and the Health Economic Evaluation Database (HEED). Qualitative results from patient and expert interviews were analysed. Hand searching of relevant conference abstracts completed the search. RESULTS: Few studies measuring the impact of ICT with deferoxamine (DFO) on patients QoL were located (n = 15). QoL domains affected included: depression; fatigue; dyspnoea; physical functioning; psychological distress; decrease in QoL during hospitalization. One theme in all articles was that oral ICT should improve QoL. No iron overload or ICT-specific QoL instruments were located in the articles. Interviews revealed that the impact of ICT on patients with thalassemia, sickle cell disease, and myelodysplastic syndromes is high. CONCLUSION: A limited number of studies assessed the impact of ICT or iron overload on QoL. All literature suggested a need for easily administered, efficacious and well tolerated oral iron overload treatments, given the impact of current ICT on adherence. Poor adherence to ICT was documented to negatively impact survival. Further research is warranted to continue the qualitative and quantitative study of QoL using validated instruments in patients receiving ICT to further understanding the issues and improve patients QoL.

Dopamine receptor supersensitivity: an outcome and index of neurotoxicity.

The characteristic feature of neurotoxicity is a definable lesion which can account for observed deficits, corresponding to loss of nuclei or axonal fibers normally comprising a specific pathway or tract. However, with ontogenetic lesions, the operative definition fails. In rats lesioned as neonates with 6-hydroxydopamine (6-OHDA), near-total destruction of dopamine- (DA-) containing nerves is produced, and this itself is definable. However, the most prominent feature of rats so-lesioned is the DA receptor supersensitivity (DARSS) that develops and then persists throughout the lifespan. DA D(1) receptors show overt supersensitivity to agonists producing vacuous chewing movements (VCMs), while D(1) receptors associated with locomotor activity have a latent supersensitivity that must be unmasked by repeated D(1) or D(2) agonist treatments - a 'priming' phenomenon. This D(1) DARSS is not usually associated in either a change in D(1) receptor number (B(max)) or affinity (K(d)). In contrast to D(1) DARSS, D(2) receptors are not so predictably supersensitized by a lesion of DA neurons. In reality, the permanently exaggerated response to an agonist by supersensitized receptors is per se a manifestation of neurotoxicity. Despite dramatic behavioral responses mediated by supersensitized receptors, DARSS has not been easy to correlate with enhanced production of second messengers or early response genes. Altered signaling (i.e., neuronal cross-talk) in defined pathways may represent the mechanism that produces so-called receptor supersensitization. Long-lived agonist-induced behavioral abnormality, with or without anatomic evidence of a neuronal lesion, is one of the products of DA D(1) receptor supersensitization -- itself an index of neurotoxicity.