A slower rate of progression of disease characterized EOMS patients, suggesting more plasticity to recover in developing CNS, but the early clinical manifestation cannot be considered a positive prognostic factor.

Amyloid-␤ (A␤) has been implicated in memory loss and disruption of synaptic plasticity observed in early-stage Alzheimer's disease. Recently, it has been shown that soluble A␤ oligomers target synapses in cultured rat hippocampal neurons, suggesting a direct role of A␤ in the regulation of synaptic structure and function. Postsynaptic density-95 (PSD-95) is a postsynaptic scaffolding protein that plays a critical role in synaptic plasticity and the stabilization of AMPA (AMPARs) and NMDA (NMDARs) receptors at synapses. Here, we show that exposure of cultured cortical neurons to soluble oligomers of A␤ 1-40 reduces PSD-95 protein levels in a dose-and time-dependent manner and that the A␤1 1-40 -dependent decrease in PSD-95 requires NMDAR activity. We also show that the decrease in PSD-95 requires cyclin-dependent kinase 5 activity and involves the proteasome pathway. Immunostaining analysis of cortical cultured neurons revealed that A␤ treatment induces concomitant decreases in PSD-95 at synapses and in the surface expression of the AMPAR glutamate receptor subunit 2. Together, these data suggest a novel pathway by which A␤ triggers synaptic dysfunction, namely, by altering the molecular composition of glutamatergic synapses.

Objective:To investigate the impact of interferon-beta (IFN␤) on disease progression in relapsing-remitting multiple sclerosis patients. Methods: A cohort of 1,504 relapsing-remitting multiple sclerosis (1,103 IFN␤-treated and 401 untreated) patients was followed for up to 7 years. Cox proportional hazards regression adjusted for propensity score inverse weighting was used to assess the differences between the two groups for three different clinical end points: secondary progression (SP) and irreversible Expanded Disability Status Scale (EDSS) scores 4 and 6. Times from first visit and from date of birth were used as survival time variables. Results: The IFN␤-treated group showed a highly significant reduction in the incidence of SP (hazard ratio [HR], 0.38, 95% confidence interval [CI], 0.24 -0.58 for time from 1st visit; HR, 0.36, 95% CI, 0.23-0.56 for time from date of birth; p Ͻ 0.0001), EDSS score of 4 (HR, 0.70, 95% CI, 0.53-0.94 for time from first visit; HR, 0.69, 95% CI, 0.52-0.93 for time from date of birth; p Ͻ 0.02), and EDSS score of 6 (HR, 0.60, 95% CI, 0.38 -0.95 for time from first visit; HR, 0.54, 95% CI, 0.34 -0.86 for time from date of birth; p Յ 0.03) when compared with untreated patients. SP and EDSS scores of 4 and 6 were reached with significant delays estimated by times from first visit (3.8, 1.7, and 2.2 years) and from date of birth (8.7, 4.6, and 11.7 years) in favor of treated patients. Sensitivity analysis confirmed findings. Interpretation: IFN-␤ slows progression in relapsing-remitting multiple sclerosis patients.Ann Neurol 2007;61: 300 -306 Few experienced in the long-term management of multiple sclerosis (MS) patients would disagree that the development of unremitting disability progression represents the major adverse event in the course of this illness, and as a consequence, it is the most important target for clinical trials to evaluate their real cost effectiveness. Whether long-term treatment with the current interferon-␤ (IFN␤) products in relapsingremitting MS (RRMS) can alter the development of long-term disability is not yet known, but it can be surmised from short-term randomized controlled trials (RCTs) 1-3 and their continuous extensions at no more than 4 years 4 and 5 years. 5 This is the stage at which immunomodulatory therapy is likely to be most effective, but then the long-term benefits on disability have to be projected from the results generated during a much earlier and briefer period in the natural disease course. Long-term RCTs would undoubtedly provide definitive evidence, but they are impractical and considered by many to be unethical. 6 More recently, further data have been collected in noncontinuous and/or retrospective, open-label extensions of the IFN␤ RCTs 7-10 ; but in these studies, the protection against bias afforded by randomization was largely lost.11 Moreover, patients enrolled in the placebo arms of RCTs do not represent the natural history of MS because they are selected for having frequent attacks during a set interval before the study....

We conducted a case-control study of 116 patients with the clinical diagnosis of Alzheimer's disease (AD) in seven Italian centers. One hundred sixteen hospital controls and 97 population controls were matched by age, sex, and region of residence to the cases. A structured questionnaire was administered to the next-of-kin of cases and controls by trained interviewers to identify possible risk factors. Genetic, viral, toxic, immunologic, medical, surgical, and personality factors were investigated. Dementia among first- or second-degree relatives and advanced age of the mother at subject's birth (age over 40) were associated with AD. Head trauma was more frequent in cases than in either hospital or population controls, but the differences were not significant. Our data did not confirm the previously reported association with antecedent thyroid disease or family history of Down's syndrome.

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Patients with multiple sclerosis have significant atrophy of both white matter (WM) and gray matter (GM); secondary progressive patients have significantly more atrophy of both WM and GM than do relapsing-remitting patients and a significantly higher lesion load (abnormal WM fraction); lesion load is related to both WM and even more to GM atrophy; lesion load and WM and GM atrophy are significantly related to Expanded Disability Status Scale score and age at onset (suggesting that the younger the age at disease onset, the worse the lesion load and brain atrophy); and GM atrophy is the most significant MRI variable in determining the final disability.

Objectives-Little is known about the aetiology of idiopathic adult onset dystonia. The Italian Movement Disorders Study Group promoted a case-control study on some hypothetical risk factors including past medical events, life events, life habits, occupational hazards, and family hystory of dystonia, parkinsonism, and tremor. Methods-Cases aVected by idiopathic adult onset dystonia (age at symptom onset >20 years, duration of disease >one year and

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