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Salloway S.,Brown University | Sperling R.,Brigham and Womens Hospital | Fox N.C.,University College London | Blennow K.,Sahlgrenska University Hospital | And 20 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Bapineuzumab, a humanized anti-amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer's disease. METHODS: We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer's disease - one involving 1121 carriers of the apolipoprotein E (APOE ) ε4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations. RESULTS: There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were -0.2 (P = 0.80) and -1.2 (P = 0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were -0.3 (P = 0.64) and 2.8 (P = 0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P = 0.62) and 0.9 (P = 0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE ε4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE ε4 allele carriers but not in noncarriers. CONCLUSIONS: Bapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE ε4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.) Copyright © 2014 Massachusetts Medical Society. Source

Yu X.,Qingdao University | Du T.,Qingdao University | Song N.,Qingdao University | He Q.,Qingdao University | And 4 more authors.
Neurology | Year: 2013

Objective: The present study aimed to evaluate alterations in the levels of iron, divalent metal transporter 1 (DMT1) with the iron-responsive element (IRE), transferrin receptor 1 (TfR1), ferroportin 1 (FPN1), and iron regulatory protein 1 (IRP1) in the temporal cortex of human brains with Parkinson disease (PD). Methods: Iron content was measured using an ICP-MS 7500CE detector. IRP1, DMT11IRE, TfR1, and FPN1 expressions were determined by Western blotting. Results: Iron content was significantly lower in the temporal cortex of patients with PD when compared with age-matched healthy controls. Unexpectedly, the levels of DMT1+IRE, TfR1, FPN1, and IRP1 were decreased in the temporal cortex in PD brains. No changes were observed in the temporal cortex of postmortem Alzheimer disease brains. Conclusions: Iron deprivation and iron-related protein dysregulation suggest that a different iron regulatory mechanism may exist, and that iron redistribution may occur between the temporal cortex and the substantia nigra of patients with PD. © 2013 American Academy of Neurology. Source

Min S.-W.,Gladstone | Min S.-W.,University of California at San Francisco | Cho S.-H.,Gladstone | Cho S.-H.,University of California at San Francisco | And 15 more authors.
Neuron | Year: 2010

Neurodegenerative tauopathies characterized by hyperphosphorylated tau include frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) and Alzheimer's disease (AD). Reducing tau levels improves cognitive function in mouse models of AD and FTDP-17, but the mechanisms regulating the turnover of pathogenic tau are unknown. We found that tau is acetylated and that tau acetylation prevents degradation of phosphorylated tau (p-tau). We generated two antibodies specific for acetylated tau and showed that tau acetylation is elevated in patients at early and moderate Braak stages of tauopathy. Histone acetyltransferase p300 was involved in tau acetylation and the class III protein deacetylase SIRT1 in deacetylation. Deleting SIRT1 enhanced levels of acetylated-tau and pathogenic forms of p-tau, probably by blocking proteasome-mediated degradation. Inhibiting p300 with a small molecule promoted tau deacetylation and eliminated p-tau associated with tauopathy. Modulating tau acetylation could be a new therapeutic strategy to reduce tau-mediated neurodegeneration. © 2010 Elsevier Inc. Source

Adler C.H.,Parkinsons Disease and Movement Disorders Center | Shill H.A.,Sun Health Research Institute | Beach T.G.,Sun Health Research Institute
Movement Disorders | Year: 2011

Background: Essential tremor (ET) is a very common disorder and proving that there is a relationship to another common movement disorder, Parkinson's disease (PD), has been debated for years. Methods: Review of the literature for links between ET and PD primarily focused on neuropathology as well as neurochemistry, epidemiology, genetics, olfactory function, and neuroimaging. Results: While there may be some evidence to suggest an increase in occurrence of PD in people who were previously diagnosed with ET, neuropathologic studies of ET with similarly assessed control subjects do not find an increase in Lewy bodies in the ET group. Studies of incidental Lewy body disease do not find an increase in ET or action tremor compared to controls. ET subjects as a group do not have neurochemical changes that are found in PD, do not respond to medications used to treat PD, are not hyposmic as is found in PD, and neuroimaging studies do not find changes of PD when groups are compared. Conclusion: The overwhelming amount of evidence suggests that any link between ET and PD is coincidental and not biological. Prospective, longitudinal cohort studies with standardized clinical and biomarker assessments followed by neuropathologic confirmation are needed. © 2011 Movement Disorder Society. Source

Sperling R.,Harvard University | Salloway S.,Butler Hospital | Brooks D.J.,Imperial College London | Tampieri D.,McGill University | And 16 more authors.
The Lancet Neurology | Year: 2012

Background: Amyloid-related imaging abnormalities (ARIA) have been reported in patients with Alzheimer's disease treated with bapineuzumab, a humanised monoclonal antibody against amyloid β. ARIA include MRI signal abnormalities suggestive of vasogenic oedema and sulcal effusions (ARIA-E) and microhaemorrhages and haemosiderin deposits (ARIA-H). Our aim was to investigate the incidence of ARIA during treatment with bapineuzumab, and evaluate associated risk factors. Methods: Two neuroradiologists independently reviewed 2572 fluid-attenuated inversion recovery (FLAIR) MRI scans from 262 participants in two phase 2 studies of bapineuzumab and an open-label extension study. Readers were masked to the patient's treatment,. APOE e{open}4 genotype, medical history, and demographics. Patients were included in risk analyses if they had no evidence of ARIA-E in their pre-treatment MRI, had received bapineuzumab, and had at least one MRI scan after treatment. We used Kaplan-Meier survival analysis to examine the distribution of incident ARIA-E from the start of bapineuzumab treatment and proportional hazards regression models to assess risk factors associated with ARIA. Findings: 210 patients were included in the risk analyses. 36 patients (17%) developed ARIA-E during treatment with bapineuzumab; 15 of these ARIA-E cases (42%) had not been detected previously. 28 of these patients (78%) did not report associated symptoms. Adverse events, reported in eight symptomatic patients, included headache, confusion, and neuropsychiatric and gastrointestinal symptoms. Incident ARIA-H occurred in 17 of the patients with ARIA-E (47%), compared with seven of 177 (4%) patients without ARIA-E. 13 of the 15 patients in whom ARIA were detected in our study received additional treatment infusions while ARIA-E were present, without any associated symptoms. Occurrence of ARIA-E increased with bapineuzumab dose (hazard ratio [HR] 2·24 per 1 mg/kg increase in dose, 95% CI 1·40-3·62; p=0·0008) and presence of. APOE e{open}4 alleles (HR 2·55 per allele, 95% CI 1·57-4·12; p=0·0001). Interpretation: ARIA consist of a spectrum of imaging findings with variable clinical correlates, and some patients with ARIA-E remain asymptomatic even if treatment is continued. The increased risk of ARIA among. APOE e{open}4 carriers, its association with high bapineuzumab dose, and its timecourse in relation to dosing suggest an association between ARIA and alterations in vascular amyloid burden. © 2012 Elsevier Ltd. Source

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