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Preclinical Stage (preclinical + stage)
Selected AbstractsDissociation between top-down attentional control and the time course of visual attention as measured by attentional dwell time in patients with mild cognitive impairmentEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2003Richard J. Perry Abstract Studies of the time course of visual attention have identified a temporary functional blindness to the second of sequentially presented stimuli in that the attentional cost of attending to one visual stimulus may lead to impairments in identifying a second stimulus presented within 500 ms of the first. This phenomenon is known as the attentional blink or attentional dwell time. The neural correlates of the attentional blink and its relationship to mechanisms that control attention are unknown. To examine this relationship we tested healthy controls and subjects in the preclinical stage of Alzheimer's disease, known as mild cognitive impairment (MCI), on a paradigm which affords quantification of both the attentional blink and the top-down control of attention. When subjects were asked to identify both a number and a letter that were rapidly and sequentially presented on a visual display, the detrimental effect that identifying the first stimulus had on the ability to identify the second served as a measure of the attentional blink. When asked to identify only one of the two stimuli, the ability to ignore the first stimulus was a function of their top-down attentional control. The MCI subjects demonstrated a normal attentional dwell time but in contrast they showed impaired top-down attentional control within the same paradigm. This dissociation suggests that these two aspects of visual attention are subserved by different neural systems. The possible neural correlates of these two attentional functions are discussed. [source] White-matter lesions along the cholinergic tracts are related to cortical sources of EEG rhythms in amnesic mild cognitive impairmentHUMAN BRAIN MAPPING, Issue 5 2009Claudio Babiloni Abstract Does impairment of cholinergic systems represent an important factor in the development of amnesic mild cognitive impairment (aMCI), as a preclinical stage of Alzheimer's disease (AD)? Here we tested the hypothesis that electroencephalographic (EEG) rhythms, known to be modulated by the cholinergic system, may be particularly affected in aMCI patients with lesions along the cholinergic white-matter tracts. Eyes-closed resting EEG data were recorded in 28 healthy elderly (Nold) and 57 aMCI patients. Lesions along the cholinergic white-matter tracts were detected with fluid-attenuated inversion recovery sequences on magnetic resonance imaging. The estimation of the cholinergic lesion was performed with a validated semi-automatic algorithm pipeline after registration to a stereotactic template, image integration with stereotactic masks of the cholinergic tracts, and normalization to intracranial volume. The aMCI patients were divided into two groups of high (MCI Ch+; N = 29; MMSE = 26.2) and low cholinergic damage (MCI Ch,; N = 28; MMSE = 26.6). EEG rhythms of interest were delta (2,4 Hz), theta (4,8 Hz), alpha 1 (8,10.5 Hz), alpha 2 (10.5,13 Hz), beta 1 (13,20 Hz), and beta 2 (20,30 Hz). Cortical EEG generators were estimated by LORETA software. As main results, (i) power of occipital, parietal, temporal, and limbic alpha 1 sources was maximum in Nold, intermediate in MCI Ch,, and low in MCI Ch+ patients; (ii) the same trend was true in theta sources. These results are consistent with the hypothesis that damage to the cholinergic system is associated with alterations of EEG sources in aMCI subjects. Hum Brain Mapp 2009. © 2008 Wiley-Liss, Inc. [source] White matter vascular lesions are related to parietal-to-frontal coupling of EEG rhythms in mild cognitive impairmentHUMAN BRAIN MAPPING, Issue 12 2008Claudio Babiloni Abstract Do cerebrovascular and Alzheimer's disease (AD) lesions represent additive factors in the development of mild cognitive impairment (MCI) as a putative preclinical stage of AD? Here we tested the hypothesis that directionality of fronto-parietal functional coupling of electroencephalographic (EEG) rhythms is relatively preserved in amnesic MCI subjects in whom the cognitive decline is mainly explained by white-matter vascular load. Resting EEG was recorded in 40 healthy elderly (Nold) and 78 amnesic MCI. In the MCI subjects, white-matter vascular load was quantified based on magnetic resonance images (0,30 visual rating scale). EEG rhythms of interest were , (2,4 Hz), , (4,8 Hz), ,1 (8,10.5 Hz), ,2 (10.5,13 Hz), ,1 (13,20 Hz), and ,2 (20,30 Hz). Directionality of fronto-parietal functional coupling of EEG rhythms was estimated by directed transfer function software. As main results, (i) fronto-parietal functional coupling of EEG rhythms was higher in magnitude in the Nold than in the MCI subjects; (ii) more interestingly, that coupling was higher at ,, ,1, ,2, and ,1 in MCI V+ (high vascular load; N = 42; MMSE = 26) than in MCI V, group (low vascular load; N = 36; MMSE= 26.7). These results are interpreted as supporting the additive model according to which MCI state would result from the combination of cerebrovascular and neurodegenerative lesions. Hum Brain Mapp 2008. © 2007 Wiley-Liss, Inc. [source] Working memory in early Alzheimer's disease: a neuropsychological reviewINTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 2 2010J. D. Huntley Abstract Background Reports of the extent of working memory (WM) impairment in early Alzheimer's disease (AD) have been inconsistent. Using the model of WM proposed by Baddeley, neuropsychological evidence for the impairment of WM in early AD is evaluated. Method Literature searches were performed using Medline, PsycINFO and Embase databases. Individual papers were then examined for additional references not revealed by computerised searches. Results Phonological loop function is intact at the preclinical and early stages of AD, becoming more impaired as the disease progresses. In mild AD, there is impairment on tasks assessing visuospatial sketchpad (VSS) function; however, these tasks also require executive processing by the central executive system (CES). There is evidence that the CES is impaired in mild AD and may be affected in the earlier preclinical stage of the disease. Episodic buffer function may be impaired but further research is required. Conclusions Future research into central executive functioning at the earliest stages of the disease, combined with further longitudinal studies, needs to be carried out. Tasks to assess the proposed functions of the episodic buffer and specific tests of the VSS suitable for AD subjects need to be developed and validated. Learning more about these processes and how they are affected in AD is important in understanding and managing the cognitive deficits seen in the early stages of AD. Copyright © 2009 John Wiley & Sons, Ltd. [source] State-of-the-Art in Longitudinal Studies on Aging: An Overview of the SupplementJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 2010Ruth M. Tappen RN The articles in this supplement are based on a conference held in January 2008 sponsored by a grant from the Robert Wood Johnson Foundation. The purpose of the conference was to summarize major findings and methodological issues in previous and ongoing longitudinal studies on aging and to identify potentially fruitful areas for future research. This article is a review and synthesis of the articles in this supplement. Each of the articles makes important contributions to summarizing existing research, identifying challenging methodological issues, or proposing areas that should be explored in future research. Three themes were identified: general improvement in the health status of the population aged 65 and older in the United States, a shift in longitudinal research on aging from a focus on the endpoints of disease to a focus on the preclinical stage and underlying mechanisms of these diseases, and contemporary developments in longitudinal research methodology. A number of practical suggestions were also drawn from the articles reviewed. [source] Early changes in renal hemodynamics in children with diabetes: Doppler sonographic findingsJOURNAL OF CLINICAL ULTRASOUND, Issue 6 2008Piernicola Pelliccia MD Abstract Purpose Although clinically evident diabetes-related microvascular complications are extremely rare in childhood, early functional and structural abnormalities may be present a few years after the onset of the disease. Renal Doppler resistance index (RI) is widely used for the evaluation of blood flow in renal parenchymal diseases. This study was designed to investigate the possible alteration of intrarenal Doppler RI in children with diabetes compared with healthy children. Methods The study was performed in 42 children with diabetes (age range, 6,18 years) and in 41 age-matched healthy controls, all having normal renal function. RI was measured with Doppler sonography in interlobular renal arteries. Results RI values were significantly greater in children with diabetes than in age-matched healthy controls (0.64 ± 0.03 versus 0.60 ± 0.04, P < 0.035). RI correlated positively with HbA1c (P < 0.001, r = 0.42) and diabetes duration (P < 0.05, r = 0.39). Conclusion Early changes in renal hemodynamics are detectable on Doppler sonography in children with diabetes without any evidence of renal dysfunction and may suggest a preclinical stage of diabetic nephropathy. © 2008 Wiley Periodicals, Inc. J Clin Ultrasound, 2008. [source] MAPK-pathway activity, Lrrk2 G2019S, and Parkinson's diseaseJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2007Linda R. White Abstract The 6055G>A mutation in the leucine-rich repeat kinase 2 (LRRK2) gene results in a G2019S substitution in the mixed-lineage kinase domain of Lrrk2, causing autosomal dominant Parkinson's disease (PD). We hypothesized the mutation alters cellular mitogen-activated protein kinase (MAPK) signalling cascades, and might be detectable in tissues other than in the brain. We therefore compared total levels and activation of the signalling proteins Src, HSP27, p38 MAPK, JNK, and ERK, in extracts of leukocytes isolated from patients with PD carrying the G2019S mutation, healthy mutation carriers, patients with idiopathic PD, and healthy controls. Phosphorylation of Src, HSP27, and JNK was reduced significantly in cell extracts from patients with G2019S-associated PD compared to healthy controls. Similarly, phosphorylation was reduced significantly in Src and HSP27 in the group of healthy carriers of the mutation, as well as in patients with idiopathic PD. Significant reductions in total Src were also observed in these three groups compared to the controls. The results of this pilot project therefore indicate significant alterations in key signalling proteins in leukocytes from patients with PD, and were most pronounced in G2019S-associated PD. Changes in MAPK-signalling may thus be common to PD pathophysiology, regardless of aetiology. Such changes may also be shown in blood samples during the preclinical stage of LRRK2 -associated PD, which could be particularly important for the development of neuroprotective strategies to delay onset, or slow progression of PD. © 2007 Wiley-Liss, Inc. [source] Pharmacokinetic/pharmacodynamic studies in drug product developmentJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2002Bernd Meibohm Abstract In the quest of ways for rationalizing and accelerating drug product development, integrated pharmacokinetic/pharmacodynamic (PK/PD) concepts provide a highly promising tool. PK/PD modeling concepts can be applied in all stages of preclinical and clinical drug development, and their benefits are multifold. At the preclinical stage, potential applications might comprise the evaluation of in vivo potency and intrinsic activity, the identification of bio-/surrogate markers, as well as dosage form and regimen selection and optimization. At the clinical stage, analytical PK/PD applications include characterization of the dose,concentration,effect/toxicity relationship, evaluation of food, age and gender effects, drug/drug and drug/disease interactions, tolerance development, and inter- and intraindividual variability in response. Predictive PK/PD applications can also involve extrapolation from preclinical data, simulation of drug responses, as well as clinical trial forecasting. Rigorous implementation of the PK/PD concepts in drug product development provides a rationale, scientifically based framework for efficient decision making regarding the selection of potential drug candidates, for maximum information gain from the performed experiments and studies, and for conducting fewer, more focused clinical trials with improved efficiency and cost effectiveness. Thus, PK/PD concepts are believed to play a pivotal role in streamlining the drug development process of the future. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:18,31, 2002 [source] Combination Nonviral Interleukin-2 Gene Immunotherapy For Head and Neck Cancer: From Bench Top to BedsideTHE LARYNGOSCOPE, Issue 3 2005Bert W. O'Malley Jr MD Abstract Objective/Hypothesis: Intralesional delivery of cytokine genes has emerged as a promising therapeutic strategy for the treatment of cancer. In addition to the therapeutic effect of the delivered cytokine gene, the components of the gene delivery system also have been shown to induce beneficial immune responses. On the basis of these principles, we hypothesized that a molecular therapy could be developed that would provide synergistic antitumor activity by way of intralesional expression of interleukin (IL)-2 from a recombinant plasmid combined with induction of endogenous interferon (IFN)-, and IL-12 cytokines by immunostimulatory DNA. Our objective in these studies was to create and optimize a novel formulation of cationic lipid and DNA that generates local production of IL-2 protein within a targeted tumor environment with concomitant induction of the antitumor cytokines IFN-, and IL-12. Study Design: Prospective laboratory drug development plan that would produce human clinical trials. Materials and Methods: Engineered bacterial plasmids containing a cytomegalovirus promoter (CMV)-IL-2 expression cassette were specifically formulated with cationic lipids and optimized for antitumor effect in a floor of mouth murine tumor model. The treated tumors were assayed for local expression of IL-2 and concurrent expression of secondary cytokines IFN-, and IL-12. Established tumors in C3H/HeJ mice were treated with various IL-2 gene formulations, and clinical and immunologic responses were evaluated. Immunologic studies were performed and included cytolytic T-cell assays and cytokine expression profiles. For human clinical trials, a phase I 10 patient formulated IL-2 gene therapy study was completed. Subsequently, two large scale, phase II multi-institutional and multi-international studies were initiated comparing non-viral IL-2 gene therapy to palliative methotrexate chemotherapy or in combination with cisplatin. Results: In the preclinical stage, maximum tumor inhibition in animal models was obtained using IL-2 plasmid formulated with 1,2-dioleyloxypropyl-3-trimethyl ammonium chloride (DOTMA):cholesterol (1:1 mol:mol) at a plasmid:lipid charge ratio of 1:0.5 (,/+). Cationic lipid formulated IL-2 plasmid significantly inhibited tumor growth compared with formulated control plasmid (P < .01) or vehicle (lactose; P < .01). Consistent with previously reported studies of the immunostimulatory activity of DNA of bacterial origin, treatment of tumors with control plasmid in cationic lipid formulation induced production of endogenous IFN-, and IL-12 but not IL-2. Treatment of tumors with formulated IL-2 plasmid produced IL-2 protein levels that were 5-fold over background and increased IFN-, by 32-fold (P < .001) and IL-12 by 5.5-fold (P < .001) compared with control plasmid formulations. The phase I human trial demonstrated dose escalation safety, which was its primary objective, and there was one anecdotal reduction in tumor size. The phase II studies have been initiated and focus on either comparing the novel nonviral IL-2 gene immunotherapy formulation alone to methotrexate or comparing IL-2 gene therapy in combination with cisplatin in recurrent or unresectable patients with head and neck squamous cell carcinoma. Conclusions: The preclinical data provided proof of principle for matching a delivered IL-2 transgene with an immunostimulatory nonviral formulation to enhance intralesional production of therapeutic cytokines for the maximization of antitumor response. Human clinical trials have demonstrated this novel therapy to be safe in the human clinical setting. Phase II trials have been initiated to assess efficacy and feasibility as a single or combination therapy for head and neck cancer. [source] Decreased cerebrospinal fluid A,42 correlates with brain atrophy in cognitively normal elderly,ANNALS OF NEUROLOGY, Issue 2 2009Anne M. Fagan PhD Objective For therapies for Alzheimer's disease (AD) to have the greatest impact, it will likely be necessary to treat individuals in the "preclinical" (presymptomatic) stage. Fluid and neuroimaging measures are being explored as possible biomarkers of AD pathology that could aid in identifying individuals in this stage to target them for clinical trials and to direct and monitor therapy. The objective of this study was to determine whether cerebrospinal fluid (CSF) biomarkers for AD suggest the presence of brain damage in the preclinical stage of AD. Methods We investigated the relation between structural neuroimaging measures (whole-brain volume) and levels of CSF amyloid-, (A,)40, A,42, tau, and phosphorylated tau181 (ptau181), and plasma A,40 and A,42 in well-characterized research subjects with very mild and mild dementia of the Alzheimer type (n = 29) and age-matched, cognitively normal control subjects (n = 69). Results Levels of CSF tau and ptau181, but not A,42, correlated inversely with whole-brain volume in very mild and mild dementia of the Alzheimer type, whereas levels of CSF A,42, but not tau or ptau181, were positively correlated with whole-brain volume in nondemented control subjects. Interpretation Reduction in CSF A,42, likely reflecting A, aggregation in the brain, is associated with brain atrophy in the preclinical phase of AD. This suggests that there is toxicity associated with A, aggregation before the onset of clinically detectable disease. Increases in CSF tau (and ptau181) are later events that correlate with further structural damage and occur with clinical onset and progression. Ann Neurol 2009;65:176,183 [source] Engineered therapeutic antibodies with improved effector functionsCANCER SCIENCE, Issue 9 2009Tsuguo Kubota In the past decade, more than 20 therapeutic antibodies have been approved for clinical use and many others are now at the clinical and preclinical stage of development. Fragment crystallizable (Fc)-dependent antibody functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and a long half-life, have been suggested as important clinical mechanisms of therapeutic antibodies. These functions are primarily triggered through direct interaction of the Fc domain with its corresponding receptors: Fc,RIIIa for ADCC, C1q for CDC, and neonatal Fc receptor for prolongation of the clearance rate. However, current antibody therapy still faces the critical issues of insufficient efficacy and the high cost of the therapeutic agents. A possible solution to these issues could be to engineer antibody molecules to enhance their antitumor activity, leading to improved therapeutic outcomes and reduced doses. Here, we review advanced Fc engineering approaches for the enhancement of effector functions, some of which are now ready for evaluation of their effectiveness in clinical trials. (Cancer Sci 2009; 100: 1566,1572) [source] | |||||||||||||