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Search Results: 1 - 10 of 469651 matches for " Sandra A. Jacobson "
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Investigational drugs for the treatment of AD: what can we learn from negative trials?
Sandra A Jacobson, Marwan N Sabbagh
Alzheimer's Research & Therapy , 2011, DOI: 10.1186/alzrt73
Abstract: In the two decades since the amyloid hypothesis was first proposed [1], a great deal of evidence has accrued in support of this mechanism in the pathogenesis of Alzheimer's disease (AD), mostly from preclinical studies of transgenic mice, autosomal dominant presenilin cases, and in vitro data supporting the neurotoxic effects of amyloid-beta (Aβ). The theoretical promise of this model, however, has yet to be realized in the world of AD therapeutics. Robust treatments still seem elusive, even with an identified therapeutic target. Others have addressed the question of why this may be the case [2,3], and this review builds on that literature.The process of drug development, from preclinical investigation through phase III study, is shown in Figure 1. Considering each phase separately helps to identify confounders that might be driving a type II error, if such an error exists in reference to new drug development for AD.Zahs and Ashe [2] reviewed mouse models of AD and made several observations in regard to translational research. These authors identified more than 300 reports of effective AD interventions based on these models. They noted, however, that none of the models is actually a complete replication of AD. In fact, what the models do simulate is a presymptomatic phase of AD, which might correspond to a time many years before a patient would present to a memory clinic or a subject would present to a clinical trial.Becker and Greig [3] identified approximately 100 candidate drugs for AD with more than 40 different mechanisms of action, and 20 of those 100 drugs showed early promise through phase II studies. Table 1 of the authors' report shows a representative sample of 16 drugs trialed within the last decade, and most of them failed because of lack of efficacy in phase III study. Trials of these drugs are reviewed in more detail below.This was the first trial in humans of an active immunotherapy approach, in which Aβ42 was introduced as an antigen to stimulate an
Essential Tremor in the Elderly and Risk for Dementia
Holly A. Shill,Joseph G. Hentz,Sandra A. Jacobson,Christine Belden,Marwan N. Sabbagh,Thomas G. Beach,Erika Driver-Dunckley,Charles H. Adler
Journal of Neurodegenerative Diseases , 2014, DOI: 10.1155/2014/328765
Abstract: The objective is to examine the risk of dementia in subjects with essential tremor (ET) involved in the Arizona Study of Aging and Neurodegenerative Disorders. All subjects were free of a neurodegenerative diagnosis at baseline and had annual motor, general neurological, and neuropsychological assessments. Subjects with ET were compared with controls for the risk of dementia. There were 83 subjects with ET and 424 subjects without tremor. Mean age at study entry was for ET and for controls. Median tremor duration was 5.2 years at study entry. Followup was a median of 5.4 years (range 0.9 to 12.1). The hazard ratio for the association between ET and dementia was 0.79 (95% CI 0.33 to 1.85). The hazard ratio for the association between tremor onset at age 65 or over, versus onset before age 65, was 2.1 (95% CI 0.24 to 18) and the hazard ratio for the association between tremor duration greater than 5 years, versus less than 5 years, was 0.46 (95% CI 0.08 to 2.6). We conclude that all elderly ET was not associated with an increased risk of dementia but that a subset of subjects with older age onset/shorter duration tremor may be at higher risk. 1. Introduction Essential tremor (ET) is a common neurological condition which increases with the age of the population and contributes to significant disability in most affected patients. Previous cross-sectional studies have shown that patients with ET may have minor cognitive deficits on formal testing although most of these older studies have been done with advanced ET patients being assessed for deep brain stimulation as treatment for tremor [1, 2]. More recently, a population study of ET demonstrated that more mildly affected, largely untreated ET individuals may be more likely to complain of memory problems and have deficits at testing [3]. This same population was more likely to have prevalent dementia, largely driven by elderly onset ET [4]. In those nondemented at baseline, incident dementia was greater in ET [5]. This study seeks to compare the risk of developing dementia in subjects with ET versus controls without tremor in a large, well-categorized cohort of individuals involved in a longitudinal aging study, the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). 2. Methods Participants without dementia or another neurodegenerative disorder at study entry and who had at least one follow-up visit were selected from the 23 May 2013 version of the AZSAND database which included 3300 subjects. All participants, both cases and controls, were initially recruited into the study largely as a result
Do CD4+ T Cell Functional Responses to Epstein–Barr Virus Provide Protective Immunity Against CNS Lymphoma in AIDS?
Mark A Jacobson
PLOS Medicine , 2007, DOI: 10.1371/journal.pmed.0040110
Introduction to Black Hole Microscopy
Theodore A. Jacobson
Physics , 1995,
Abstract: The aim of these notes is both to review the standard understanding of the Hawking effect, and to discuss the modifications to this understanding that might be required by new physics at short distances. The fundamentals of the Unruh effect are reviewed, and then the Hawking effect is explained as a ``gravitational Unruh effect", with particular attention to the state-dependence of this picture. The order of magnitude of deviations from the thermal spectrum of Hawking radiation is estimated under various hypotheses on physics at short distances. The behavior of black hole radiation in a linear model with altered short distance physics---the Unruh model---is discussed in detail. [Based on lectures given at the First Mexican School on Gravitation and Mathematical Physics, Guanajuato, December 1994.]
Small asteroid system evolution
Seth A. Jacobson
Physics , 2014, DOI: 10.1017/S174392131400800X
Abstract: Observations with radar, photometric and direct imaging techniques have discovered that multiple asteroid systems can be divided clearly into a handful of different morphologies, and recently, the discovery of small unbound asteroid systems called asteroid pairs have revolutionized the study of small asteroid systems. Simultaneously, new theoretical advances have demonstrated that solar radiation dictates the evolution of small asteroids with strong implications for asteroid internal structure. We review our current understanding of how small asteroid systems evolve and point to the future.
Multiple origins of asteroid pairs
Seth A. Jacobson
Physics , 2015,
Abstract: Rotationally fissioned asteroids produce unbound daughter asteroids that have very similar heliocentric orbits. Backward integration of their current heliocentric orbits provides an age of closest proximity that can be used to date the rotational fission event. Most asteroid pairs follow a predicted theoretical relationship between the primary spin period and the mass ratio of the two pair members that is a direct consequence of the YORP-induced rotational fission hypothesis. If the progenitor asteroid has strength, asteroid pairs may have high mass ratios with possibly fast rotating primaries. However, secondary fission leaves the originally predicted trend unaltered. We also describe the characteristics of pair members produced by four alternative routes from a rotational fission event to an asteroid pair. Unlike direct formation from the event itself, the age of closest proximity of these pairs cannot generally be used to date the rotational fission event since considerable time may have passed.
From the global signature to higher signatures
Jeremy A. Jacobson
Mathematics , 2014,
Abstract: Let $X$ be an algebraic variety over the field of real numbers $\mathbb{R}$. We use the signature of a quadratic form to produce "higher" global signatures relating the derived Witt groups of $X$ to the singular cohomology of the real points $X(\mathbb{R})$ with integer coefficients. We also study the global signature ring homomorphism and use the powers of the fundamental ideal in the Witt ring to prove an integral version of a theorem of Raman Parimala and Jean Colliot-Thelene on the mod 2 signature. Furthermore, we obtain an Atiyah-Hirzebruch spectral sequence for the derived Witt groups of $X$ with 2 inverted. Using this spectral sequence, we provide a bound on the ranks of the derived Witt groups of $X$ in terms of the Betti numbers of $X(\mathbb{R})$. We apply our results to answer a question of Max Karoubi on boundedness of torsion in the Witt group of $X$. Throughout the article, the results are proved for a wide class of schemes over an arbitrary base field of characteristic different from 2 using real cohomology in place of singular cohomology.
Quantitative Appraisal of Ventricular Cerebrospinal Fluid Biomarkers in Neuropathologically Diagnosed Parkinson's Disease Cases Lacking Alzheimer's Disease Pathology
Chera L. Maarouf, Thomas G. Beach, Charles H. Adler, Michael Malek-Ahmadi, Tyler A. Kokjohn, Brittany N. Dugger, Douglas G. Walker, Holly A. Shill, Sandra A. Jacobson, Marwan N. Sabbagh, Alex E. Roher and Arizona Parkinson’s Disease Consortium
Biomarker Insights , 2012, DOI: 10.4137/BMI.S11422
Abstract: Identifying biomarkers that distinguish Parkinson’s disease (PD) from normal control (NC) individuals has the potential to increase diagnostic sensitivity for the detection of early-stage PD. A previous proteomic study identified potential biomarkers in postmortem ventricular cerebrospinal fluid (V-CSF) from neuropathologically diagnosed PD subjects lacking Alzheimer’s disease (AD) neuropathology. In the present study, we assessed these biomarkers as well as p-tau181, Aβ42, and S100B by ELISA in PD (n = 43) and NC (n = 49) cases. The p-tau181/A 42 ratio and ApoA-1 showed statistically significant differences between groups. Multiple regression analysis demonstrated that p-tau181/Aβ42 had a significant odds ratio: OR = 1.42 (95% confidence interval [CI], 1.12–1.84), P = 0.006. Among the molecules investigated, intriguing correlations were observed that require further investigation. Our results suggest co-existent AD CSF biomarkers within the PD group notwithstanding that it was selected to minimize AD neuropathological lesions.
SMG1 Identified as a Regulator of Parkinson’s Disease-Associated alpha-Synuclein through siRNA Screening
Adrienne Henderson-Smith, Donald Chow, Bessie Meechoovet, Meraj Aziz, Sandra A. Jacobson, Holly A. Shill, Marwan N. Sabbagh, John N. Caviness, Charles H. Adler, Erika D. Driver-Dunckley, Thomas G. Beach, Hongwei Yin, Travis Dunckley
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077711
Abstract: Synucleinopathies are a broad class of neurodegenerative disorders characterized by the presence of intracellular protein aggregates containing α-synuclein protein. The aggregated α-synuclein protein is hyperphosphorylated on serine 129 (S129) compared to the unaggregated form of the protein. While the precise functional consequences of S129 hyperphosphorylation are still being clarified, numerous in vitro and in vivo studies suggest that S129 phosphorylation is an early event in α-synuclein dysfunction and aggregation. Identifying the kinases and phosphatases that regulate this critical phosphorylation event may ultimately prove beneficial by allowing pharmacological mitigation of synuclein dysfunction and toxicity in Parkinson’s disease and other synucleinopathies. We report here the development of a high-content, fluorescence-based assay to quantitate levels of total and S129 phosphorylated α-synuclein protein. We have applied this assay to conduct high-throughput loss-of-function screens with siRNA libraries targeting 711 known and predicted human kinases and 206 phosphatases. Specifically, knockdown of the phosphatidylinositol 3-kinase related kinase SMG1 resulted in significant increases in the expression of pS129 phosphorylated α-synuclein (p-syn). Moreover, SMG1 protein levels were significantly reduced in brain regions with high p-syn levels in both dementia with Lewy bodies (DLB) and Parkinson’s disease with dementia (PDD). These findings suggest that SMG1 may play an important role in increased α-synuclein pathology during the course of PDD, DLB, and possibly other synucleinopathies.
Observations of atmospheric gravity waves by radio interferometry: are results biased by the observational technique?
C. Mercier,A. R. Jacobson
Annales Geophysicae (ANGEO) , 2003,
Abstract: In this paper we present a quantitative comparison between a large data base of medium-scale atmospheric gravity waves (AGWs) observed by radio interferometry of transionospheric radio sources and the results of a numerical simulation of the observed effects. The simulation includes: (i) the propagation and dissipation of AGWs up to ionospheric heights and (ii) the calculation of the subsequent slant TEC perturbations integrated along the path to the radio sources. We show that the observed azimuthal distribution of AGWs can be deeply biased. Predicted results are found to be consistent with previous extensive observations using radio beacons aboard geostationary satellites. These observations are rediscussed in view of the present predictions.
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