Sun Health Research Institute

Sun City, AZ, United States

Sun Health Research Institute

Sun City, AZ, United States
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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.


Sabbagh M.N.,Sun Health Research Institute | Sabbagh M.N.,Santa Fe Institute | Agro A.,TransTech Pharma | Bell J.,Pfizer | And 3 more authors.
Alzheimer Disease and Associated Disorders | Year: 2011

Objective: To evaluate the safety and tolerability of PF-04494700, an oral inhibitor of receptor for advanced glycation end products, in patients with mild-to-moderate dementia of the Alzheimer type. Methods: Patients aged 50 years and older who met the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria for Alzheimer disease with an Mini-Mental State Examination (MMSE) score between 12 and 26 (inclusive) were randomized to 10 weeks of double-blind treatment with either a 10 mg "low dose" of PF-04494700 (after a 6-d loading dose of 30 mg/d), a 20 mg "high dose" of PF-04494700 (after a loading dose of 60 mg/d), or placebo. Safety measures included adverse events, laboratory tests, vital signs, and 12-lead electrocardiogram. Results: Twenty-seven patients received PF-04494700 30/co mg (female: 63%; mean age: 74.6 y; mean MMSE: 21.1), 28 patients received PF-04494700 60/20 mg (female: 57%; mean age: 76.6 y; mean MMSE: 21.6), and 12 patients received placebo (female: 67%; mean age: 74.1 y; mean MMSE: 19.2). A higher proportion of patients completed 10 weeks of double-blind treatment on both the "low-dose" regimen of PF-04494700 (88.9%) and the "high-dose" regimen (85.7%) than patients who were on placebo (66.7%). Discontinuation owing to adverse events and incidence of severe adverse events, respectively, were lower in the "low-dose" regimen (7.4%, 11.1%) and the "high-dose" regimen (3.6%, 10.7%) compared with placebo (25.0%, 16.7%). There were no clinically meaningful differences in vital signs, laboratory test results, or mean electrocardiogram parameters in patients treated with PF-04494700. PF-04494700 had no consistent effect on plasma levels of β-amyloid, inflammatory biomarkers, or secondary cognitive outcomes. Conclusions: Ten weeks of treatment with PF-04494700 was safe and well tolerated in patients with mild-to-moderate Alzheimer disease, indicating the feasibility of a larger long-term efficacy trial. Copyright © 2011 by Lippincott Williams & Wilkins.


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.


Salloway S.,Brown University | Sperling R.,Brigham and Women's 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.


Sperling R.,Harvard University | Salloway S.,Butler Hospital | Brooks D.J.,Imperial College London | Tampieri D.,McGill University | And 15 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.


Long J.,Sun Health Research Institute | Long J.,Xi'an University of Science and Technology | He P.,Roskamp Institute | Shen Y.,Roskamp Institute | And 2 more authors.
Journal of Alzheimer's Disease | Year: 2012

Accumulating evidence suggests that mitochondria are important targets for the actions of estrogens and studies indicated that localization of estrogen receptor β (ERβ) in neuronal mitochondrial (mtERβ) might directly affect neuronal mitochondrial function in vitro. However, it is unknown what expression levels and how important mtERβ is in the human brain, particularly in a brain with Alzheimer's disease (AD). In the present study, using rapidly autopsied human brain tissue, we found that the frontal cortices of female AD patients exhibited significantly reduced mtERβ, along with reduced mitochondrial cytochrome C oxidase activity, and increased protein carbonylation compared to that in normal controls. The correlation between mtERβ expression and mitochondrial cytochrome C oxidase activity in the female human brain is significant. To understand the possible mechanisms of mtERβ in AD-related mitochondrial dysfunction, using ERβKO mice as a model, we found that lack of ERβ enhanced brain reactive oxygen species generation and reduced mitochondrial membrane potential under Aβ peptide insult compared to brain mitochondria from wild-type control mice. Our studies, for the first time, demonstrated neuronal mtERβ expression in the human brain and the deficiency of mtERβ in the female AD brain is associated with the dysfunction of mitochondria. Our results from ERβKO mice demonstrated that ERβ depletion-induced mitochondrial dysfunction is mediated through increasing reactive oxygen generation and reduction of mitochondria membrane potential. These results indicate that ERβ depletion impairs mitochondrial function in mice, and reduction of brain mtERβ may significantly contribute to the mitochondrial dysfunction involved in AD pathogenesis in women. © 2012 -IOS Press and the authors.


van den Berge S.A.,Institute of the Royal Netherlands Academy of science | Middeldorp J.,Institute of the Royal Netherlands Academy of science | Eleana Zhang C.,Institute of the Royal Netherlands Academy of science | Curtis M.A.,University of Auckland | And 7 more authors.
Aging Cell | Year: 2010

A main neurogenic niche in the adult human brain is the subventricular zone (SVZ). Recent data suggest that the progenitors that are born in the human SVZ migrate via the rostral migratory stream (RMS) towards the olfactory bulb (OB), similar to what has been observed in other mammals. A subpopulation of astrocytes in the SVZ specifically expresses an assembly-compromised isoform of the intermediate filament protein glial fibrillary acidic protein (GFAP-δ). To further define the phenotype of these GFAP-δ expressing cells and to determine whether these cells are present throughout the human subventricular neurogenic system, we analysed SVZ, RMS and OB sections of 14 aged brain donors (ages 74-93). GFAP-δ was expressed in the SVZ along the ventricle, in the RMS and in the OB. The GFAP-δ cells in the SVZ co-expressed the neural stem cell (NSC) marker nestin and the cell proliferation markers proliferating cell nuclear antigen (PCNA) and Mcm2. Furthermore, BrdU retention was found in GFAP-δ positive cells in the SVZ. In the RMS, GFAP-δ was expressed in the glial net surrounding the neuroblasts. In the OB, GFAP-δ positive cells co-expressed PCNA. We also showed that GFAP-δ cells are present in neurosphere cultures that were derived from SVZ precursors, isolated postmortem from four brain donors (ages 63-91). Taken together, our findings show that GFAP-δ is expressed in an astrocytic subpopulation in the SVZ, the RMS and the OB. Importantly, we provide the first evidence that GFAP-δ is specifically expressed in longterm quiescent cells in the human SVZ, which are reminiscent of NSCs. © 2010 The Authors Journal compilation © Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 2010.


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.


He P.,Roskamp Institute | He P.,Sun Health Research Institute | Liu Q.,Barrow Neurological Institute | Wu J.,Barrow Neurological Institute | And 2 more authors.
FASEB Journal | Year: 2012

The distribution of postsynaptic glutamate receptors has been shown to be regulated by proimmunocytokine tumor necrosis factor α (TNF-α) signaling. The role of TNF-α receptor subtypes in mediating glutamate receptor expression, trafficking, and function still remains unclear. Here, we report that TNF receptor subtypes (TNFR1 and TNFR2) differentially modulate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) clustering and function in cultured cortical neurons. We find that genetic deletion of TNFR1 decreases surface expression and synaptic localization of the AMPAR GluA1 subunit, reduces the frequency of miniature excitatory postsynaptic current (mEPSC), and reduces AMPA-induced maximal whole-cell current. In addition, these results are not observed in TNFR2-deleted neurons. The decreased AMPAR expression and function in TNFR1- deleted cells are not significantly restored by short (2 h) or long (24 h) term exposure to TNF-α. In TNFR2- deleted cells, TNF-α promotes AMPAR trafficking to the synapse and increases mEPSC frequency. In the present study, we find no significant change in the GluN1 subunit of NMDAR clusters, location, and mEPSC. This includes applying or withholding the TNF-α treatment in both TNFR1- and TNFR2-deleted neurons. Our results indicate that TNF receptor subtype 1 but not 2 plays a critical role in modulating AMPAR clustering, suggesting that targeting TNFR1 gene might be a novel approach to preventing neuronal AMPAR-mediated excitotoxicity. © FASEB.


Mastroeni D.,Sun Health Research Institute | Grover A.,Sun Health Research Institute | Delvaux E.,Sun Health Research Institute | Whiteside C.,Sun Health Research Institute | And 2 more authors.
Neurobiology of Aging | Year: 2010

DNA methylation is a vital component of the epigenetic machinery that orchestrates changes in multiple genes and helps regulate gene expression in all known vertebrates. We evaluated immunoreactivity for two markers of DNA methylation and eight methylation maintenance factors in entorhinal cortex layer II, a region exhibiting substantial Alzheimer's disease (AD) pathology in which expression changes have been reported for a wide variety of genes. We show, for the first time, neuronal immunoreactivity for all 10 of the epigenetic markers and factors, with highly significant decrements in AD cases. These decrements were particularly marked in PHF1/PS396 immunoreactive, neurofibrillary tangle-bearing neurons. In addition, two of the DNA methylation maintenance factors, DNMT1 and MBD2, have been reported also to interact with ribosomal RNAs and ribosome synthesis. Consistent with these findings, DNMT1 and MBD2, as well as p66α, exhibited punctate cytoplasmic immunoreactivity that co-localized with the ribosome markers RPL26 and 5.8. s rRNA in ND neurons. By contrast, AD neurons generally lacked such staining, and there was a qualitative decrease in RPL26 and 5.8. s rRNA immunoreactivity. Collectively, these findings suggest epigenetic dysfunction in AD-vulnerable neurons. © 2008 Elsevier Inc.

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