E. Tagliabue

Glutamate transporters in platelets: EAAT1 decrease in aging and in Alzheimer's disease

Platelets release glutamate upon activation and are an important clearance system of the amino acid from blood, through high-affinity glutamate uptake, similar to that described in brain synaptosomes. Since platelet glutamate uptake is decreased in neurodegenerative disorders, we performed a morphological and molecular characterization of platelet glutamate transporters. The three major brain glutamate transporters EAAT1, EAAT2 and EAAT3 are expressed in platelets, with similar molecular weight, although at lower density than brain. A Na(+)-dependent-high-affinity glutamate uptake was competitively inhibited by known inhibitors but not by dihydrokainic acid, suggesting platelet EAAT2 does not play a major role in glutamate uptake at physiological conditions. We observed decreased glutamate uptake V(max), without modification of transporter affinity, in aging, which could be linked to the selective decrease of EAAT1 expression and mRNA. Moreover, in AD patients we found a further EAAT1 reduction compared to age-matched controls, which could explain the decrease of platelet uptake previously described. Platelet glutamate transporters may be used as peripheral markers to investigate the role of glutamate in patients with neuropsychiatric disorders.

Fibroblast glutamate transport in aging and in AD: correlations with disease severity

Altered glutamate transport and aberrant EAAT1 expression were shown in Alzheimers disease (AD) brains. It is presently unknown whether these modifications are a consequence of neurodegeneration or play a pathogenetic role. However, recent findings of decreased glutamate uptake, EAAT1 protein and mRNA in AD platelets suggest that glutamate transporter modifications may be systemic and might explain the decreased glutamate uptake. We now used primary fibroblast cultures from 10 AD patients to further investigate the specific involvement of glutamate transporters in this disorder and in normal aging. Decreased glutamate uptake (p<0.001), EAAT1 expression (p<0.05) and mRNA (p<0.01) were observed in aged people, compared to younger controls. In AD fibroblasts, compared to age-matched controls, we observed further reductions of glutamate uptake (p<0.0005) and EAAT1 expression (p<0.005), while EAAT1 mRNA increase (p<0.001) was shown. EAAT1 parameters were mutually correlated (p<0.01) and correlations were shown with dementia severity (p<0.05 MMSE-expression, p<0.005 MMSE-mRNA). We suggest fibroblast cultures as possible ex vivo peripheral model to study the glutamate involvement and possible molecular and therapeutic targets in AD.

Pixantrone (BBR2778) reduces the severity of experimental allergic encephalomyelitis

Pixantrone is less cardiotoxic and is similarly effective to mitoxantrone (MTX) as an antineoplastic drug. In our study, pixantrone reduced the severity of acute and decreased the relapse rate of chronic relapsing experimental allergic encephalomyelitis (EAE) in rats. A marked and long-lasting decrease in CD3+, CD4+, CD8+ and CD45RA+ blood cells and reduced anti-MBP titers were observed with both pixantrone and MTX. In vitro mitogen- and antigen-induced T-cell proliferation tests of human and rodents cells evidenced that pixantrone was effective at concentrations which can be effectively obtained after i.v. administration in humans. Cardiotoxicity was present only in MTX-treated rats. The effectiveness and the favorable safety profile makes pixantrone a most promising immunosuppressant agent for clinical use in multiple sclerosis (MS).

Extracorporeal photochemotherapy: A safety and tolerability pilot study with preliminary efficacy results in refractory relapsing-remitting multiple sclerosis

Extracorporeal photochemotherapy (ECP) is an immunomodulating procedure consisting of autologous reinfusion of peripheral blood mononuclear cells (PBMC) after direct exposure to 8-methoxy-psoralen and UV-A. It has been described as a successful treatment for different T-cell-mediated diseases and preliminary results suggest that ECP might be effective in the treatment of relapsing–remitting multiple sclerosis, but does not significantly alter the course of the progressive form of MS. In this study, we report the safety data and some preliminary efficacy evidence obtained using ECP in the treatment of five patients with refractory relapsing-remitting (RR) MS: in most cases ECP induced a reduction in the relapse rate and an EDSS stabilisation, with an apparent general MRI stabilisation. In conclusion, our results confirm ECP safety and tolerability and suggest that this treatment might be useful as a therapeutic alternative in the subgroup of RRMS patients not responsive to or not eligible for traditional immunomodulating or immunosuppressive treatments.

Diagnostic Validity of Optic Disc and Retinal Nerve Fiber Layer Evaluations in Detecting Structural Changes after Optic Neuritis

PURPOSE To assess the diagnostic validity of morphometric examination of the optic disc and retinal nerve fiber layer (RNFL) thickness to detect permanent structural changes after retrobulbar optic neuritis (ON). DESIGN Evaluation of a diagnostic test. PARTICIPANTS Twenty-five patients with a history of retrobulbar ON and 29 disease-free controls. METHODS The optic discs were evaluated by means of confocal scanning laser ophthalmoscopy (Heidelberg Retinal Tomograph [HRT III]), and RNFL thickness by means of scanning laser polarimetry (GDx), and optical coherence tomography (OCT). Vision function was assessed in all subjects by testing visual acuity, contrast sensitivity, color vision, visual field (VF), and visual evoked potentials (VEPs). Statistical comparisons were made between the affected (ON) and unaffected eyes (non-ON) of the patients with ON, and between these eyes and control eyes (Mann-Whitney test and Wilcoxons test). Receiver operating characteristic (ROC) curves, and sensitivity and specificity in discriminating ON from control eyes, were calculated for the significant parameters. Correlations between the tests were calculated by means of Spearmans correlation coefficient. MAIN OUTCOME MEASURES We compared OCT, GDx, HRT, and visual testing results in ON eyes versus control eyes. RESULTS All of the visual function test parameters and RNFL thickness (GDx and OCT) were significantly different between the ON eyes and both the non-ON and control eyes (P<0.01), and there were significant differences in some GDx parameters between the non-ON and control eyes. There were no significant differences in the HRT parameters. The ROC curves indicated that the greatest diagnostic validity was associated with the GDx nerve fiber indicator (AUC, 0.92; sensitivity, 0.80; specificity, 0.97 using a cutoff point of 20.5 between ON and non-ON eyes), and OCT temporal thickness (AUC, 0.92; sensitivity, 0.72; specificity, 0.95 using a cutoff point of 51.5 microm). CONCLUSIONS When investigating permanent damage after ON, RNFL thickness is a promising biomarker. The GDx and OCT are reliable, noninvasive, user-friendly devices; both show good diagnostic validity and good correlations with functional tests in discriminating affected from unaffected eyes. Retinal nerve fiber layer thinning in non-ON eyes should be further studied as a possible subclinical indicator of disease.

Isolated bilateral anterior optic neuritis following chickenpox in an immunocompetent adult.

Chickenpox may lead to several different neurological complications, but optic neuritis has rarely been described; in particular, only one case of isolated bilateral anterior optic neuritis (AON) in an immune-competent adult has so far been reported. We describe a second case of this type and consider similarities and differences between our patient and all other cases of AON following chickenpox. Then, we discuss the therapeutic role of steroids and advance the hypothesis of different pathogenetic pathways in immune-competent and immunecompromised subjects.

Third cranial nerve palsy? Look for a sicca syndrome.

Sjogrens syndrome (SS) is a systemic autoimmune disorder, and neurological involvement may frequently occur. Here we describe a 79-year-old woman who came to our attention for a sudden right incomplete 3rd cranial nerve palsy. Following extensive investigations, a diagnosis of primary SS was reached, and the patient recovered after treatment with ev Ig and steroids. Therefore, we suggest that SS should be considered in apparently idiopathic 3rd cranial nerve palsies, since, with the appropriate treatment, they might be transient and reversible.

An apparently sporadic case of oculopharyngeal muscular dystrophy: the first Italian report.

Here we report the case of a 73-year-old Italian woman affected by genetically confirmed oculopharyngeal muscular dystrophy (OPMD) with a negative family history. As OPMD is usually transmitted as an autosomal-dominant meiotically stable trait, this case allows us to suggest that putative de novo OPMD mutations might occur more frequently than previously thought; moreover, when compatible with a proper clinical phenotype, OPMD might be included in the differential diagnosis even in the absence of a positive family history.

Effects of pixantrone on immune-cell function in the course of acute rat experimental allergic encephalomyelitis

Pixantrone is an immunesuppressor similar to mitoxantrone but with lower cardiotoxicity. We evaluated the effect of pixantrone on B cells and lymphomononuclear cells in the course of acute EAE. Pixantrone reduced the number of B cells and suppressed myelin basic protein (MBP) specific IgG production. In vitro, pixantrone induced apoptosis of rat B lymphocytes in a way similar to mitoxantrone. In addition, pixantrone inhibited antigen specific and mitogen induced lymphomononuclear cell proliferation, as well as IFN-gamma production, during EAE. These findings suggest a similar mechanism of action for pixantrone and mitoxantrone on the effector function of lymphomonocyte B and T cells.

Is elevated post-methionine load homocysteinaemia a risk factor for cervical artery dissection?

Cervical artery dissection (CAD) represents one of the most frequent causes of stroke in young adults. Although traumas are known to be main risk factors for developing CAD, spontaneous idiopathic forms, probably related to arterial wall diseases, have been described as well, actually representing the major quota. Interestingly, recent studies indicate that even mild elevation of basal plasma homocysteine (Hcy) levels might be a risk factor for spontaneous CAD [1–3], possibly by favouring the damage and/or the dysfunction of the endothelium [4]. However, plasma levels of post-methionine load Hcy have never been investigated in spontaneous CAD patients. As a matter of fact, increased Hcy plasma levels after methionine load has been reported to be a risk factor for stroke in young adults, while no differences were shown for basal levels with respect to healthy agematched controls [5]. Notably, some authors suggest that the post-methionine load test might help identifying those patients harbouring a putative state of “methionine intolerance” that might be clinically relevant, although not associated to elevated basal Hcy plasma levels [6]. Here we report the case of a patient who came to our attention for a sudden orbito-frontal pain unresponsive to non-steroid anti-inflammatory drugs. A brain MRI suggested a CAD, which was subsequently confirmed by conventional angiography. No known risk factors for CAD were present, leading to the diagnosis of spontaneous CAD. Basal Hcy plasma level was measured 10 days after admission and was normal (11.5 μmol/l; normal range: 10–15 μmol/l), while post-methionine load Hcy plasma level (240 min following oral administration of 0.1 g/kg methionine) was 37.2 ?mol/l (normal range: up to 30 μmol/l). Although it is not possible to rule out that elevated basal and/or post-load Hcy plasma levels might be a consequence of the acute event, one study reported elevated basal levels up to 10 years following CAD [2]. Therefore, the present, purely anecdotal, case report, if replicated, might prompt to design a clinical study for specifically addressing the role of elevated post-methionine load Hcy plasma levels as an independent risk factor for CAD. In conclusion, we would like to suggest that postmethionine load Hcy and, possibly, folate supplementation for secondary prevention, as previously suggested for hyperhomocysteinaemia states [7], might deserve further clinical investigation in CAD patients, possibly helping to shed more light on the still unknown pathogenesis of this disease.