E Giacobini

University of Geneva, Genève, Geneva, Switzerland

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Publications (227)774.19 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: In cognitively intact individuals and patients with Alzheimer’s disease (AD) the formation of neurofibrillary tangles (NFTs), senile plaques (SPs), and the synaptic loss characterizes the neuropathology of brain aging. There is a differential cortical vulnerability to the degenerative process in extreme brain aging. In the oldest-old population the distribution and the severity of NFTs and SPs could be different compared to younger persons.
    Advances in Experimental Medicine and Biology 01/2015; 822:17. DOI:10.1007/978-3-319-08927-0_4 · 2.01 Impact Factor
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    ABSTRACT: Neuropathological hallmarks of Alzheimer's disease (AD) include tangles (NFT) and beta amyloid (Aβ) plaques. Despite numerous neuropathological studies that assessed the relationship of cognitive decline with neuropathologic lesions, their correlation still remains unclear. NFTs and Aβ plaques have been widely implicated and described in normal aging. The number of NFTs in the CA1 and the entorhinal cortex seems to be more closely related to cognitive status, compared to the amyloid load whose role still remains controversial in the AD. In this review, we refer to our main studies performed in Geneva during the past two decades attempting to assess the correlation of pathology with clinical expression. The theory of cognitive reserve has been proposed for further understanding of interindividual differences in terms of compensation despite the presence of pathological lesions. The increasing prevalence of the AD, the limitations of actual treatments, as well as the high public cost reflect the imperative need for better therapeutic and early diagnosis strategies in the future.
    Advances in Experimental Medicine and Biology 01/2015; 821:11-7. DOI:10.1007/978-3-319-08939-3_6 · 2.01 Impact Factor
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    ABSTRACT: Worldwide multidisciplinary translational research has led to a growing knowledge of the genetics and molecular pathogenesis of Alzheimer's disease (AD) indicating that pathophysiological brain alterations occur decades before clinical signs and symptoms of cognitive decline can be diagnosed. Consequently, therapeutic concepts and targets have been increasingly focused on early-stage illness before the onset of dementia; and distinct classes of compounds are now being tested in clinical trials. At present, there is a growing consensus that therapeutic progress in AD delaying disease progression would significantly decrease the expanding global burden. The evolving hypothesis- and evidence-based generation of new diagnostic research criteria for early-stage AD has positively impacted the development of clinical trial designs and the characterization of earlier and more specific target populations for trials in prodromal as well as in pre- and asymptomatic at-risk stages of AD.
    Expert Review of Neurotherapeutics 12/2014; 15(1):1-23. DOI:10.1586/14737175.2015.995637 · 2.83 Impact Factor
  • Ezio Giacobini
    Neurobiology of Aging 03/2014; 35:S8-S9. DOI:10.1016/j.neurobiolaging.2014.01.061 · 4.85 Impact Factor
  • Constantin Bouras · A. Savioz · E. Giacobini
    Neurobiology of Aging 03/2014; 35. DOI:10.1016/j.neurobiolaging.2014.01.040 · 4.85 Impact Factor
  • Source
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    ABSTRACT: The modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild-to-moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or ‘mild cognitive impairment due to Alzheimer's disease’, for drugs considered to be disease modifying. The duration of trials has remained at 6–12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early-stage Alzheimer's disease trial samples using biomarkers and phase-specific outcomes. In conclusion, validated drug targets for Alzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late-phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.
    Journal of Internal Medicine 03/2014; 275(3). DOI:10.1111/joim.12191 · 5.79 Impact Factor
  • Source
    Ana Martínez · Debomoy K Lahiri · Ezio Giacobini · Nigel H Greig
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    ABSTRACT: Although significant accomplishments have been made in research to understand, diagnose and treat Alz-heimer's disease (AD) and its prequel, mild cognitive impairment, over the last two decades, a huge amount more remains to be achieved to impact this incurable, terminal disease that afflicts an estimated 26.6 million people worldwide. Increas-ing evidence indicates that early diagnosis will be fundamental to maximizing treatment benefits. Moreover, mechanisti-cally-based, hypothesis-driven treatment strategies are now emerging to hopefully spearhead future therapy. The cross-fertilization of ideas from multiple disciplines will prove key to optimize strategies and translate them to meaningful clini-cal utility, and forms the basis of the current issue focused on "Advances in Alzheimer therapy". The 10th International Hong Kong/Springfield Pan-Asian Symposium on Advances in Alzheimer Therapy, held in Kowloon, Hong Kong, on February 28, 29 and March 1, 2008, for the first time integrated across East and West more than 1200 basic and clinical research scientists/physicians to impart the latest information to unravel the origin and patho-genesis of Alzheimer's disease (AD) and to both discuss and highlight improvements towards its diagnosis and potential treatment by established as well as novel strategies. This unique biennial symposium series continues to provide a priceless mechanism to bring under the same roof a dichot-omy of scientific interests and expertise to specifically focus them on AD and related dementias and to disseminate the most current knowledge on recent advances in its potential therapy. AD is now recognized as an incurable, degenerative and terminal disease that is global – afflicting an estimated 26.6 million people worldwide in 2006, with the number growing in an unabated and frightening manner.
  • dressNature Reviews Drug Discovery 12/2013; 13(2). DOI:10.1038/nrd3842-c2 · 37.23 Impact Factor
  • Ezio Giacobini · Gabriel Gold
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    ABSTRACT: Disease-modifying treatments for Alzheimer disease (AD) have focused mainly on reducing levels of amyloid-β (Aβ) in the brain. Some compounds have achieved this goal, but none has produced clinically meaningful results. Several methodological issues relating to clinical trials of these agents might explain this failure; an additional consideration is that the amyloid cascade hypothesis-which places amyloid plaques at the heart of AD pathogenesis-does not fully integrate a large body of data relevant to the emergence of clinical AD. Importantly, amyloid deposition is not strongly correlated with cognition in multivariate analyses, unlike hyperphosphorylated tau, neurofibrillary tangles, and synaptic and neuronal loss, which are closely associated with memory deficits. Targeting tau pathology, therefore, might be more clinically effective than Aβ-directed therapies. Furthermore, numerous immunization studies in animal models indicate that reduction of intracellular levels of tau and phosphorylated tau is possible, and is associated with improved cognitive performance. Several tau-related vaccines are in advanced preclinical stages and will soon enter clinical trials. In this article, we present a critical analysis of the failure of Aβ-directed therapies, discuss limitations of the amyloid cascade hypothesis, and suggest the potential value of tau-targeted therapy for AD.
    Nature Reviews Neurology 11/2013; 9(12). DOI:10.1038/nrneurol.2013.223 · 14.10 Impact Factor
  • Constantin Bouras · Eniko Kovari · Ezio Giacobini
    Alzheimer's and Dementia 07/2013; 9(4):P442. DOI:10.1016/j.jalz.2013.05.880 · 17.47 Impact Factor
  • Source
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    ABSTRACT: An international task force of investigators from academia, industry, nonprofit foundations, and regulatory agencies met in Monte Carlo, Monaco, on October 31, 2012, to review lessons learned from the recent bapineuzumab and solanezumab trials, and to incorporate insights gained from these trials into future clinical studies. Although there is broad consensus that Alzheimer’s disease (AD) should be treated during its earliest stages, the concept of secondary prevention has evolved to be described more accurately as treatment of preclinical, presymptomatic, or early AD. There continues to be a strong emphasis on biomarkers and a need for new biomarkers; however, there has also been a realization, based on completed trials, that the most reliable indicator of clinical efficacy across the entire spectrum of disease from asymptomatic to AD dementia is likely a measure of cognition. The task force made many recommendations that should improve the likelihood of success in future trials, including larger phase 2 or combined phase 2/phase 3 studies, clear evidence of target engagement in the central nervous system, evidence of downstream effects on biomarkers before initiating phase 3 studies, consideration of adaptive and targeted trial designs, and use of sensitive measures of cognition as the most robust indicator of treatment benefit.
    Alzheimer's and Dementia 07/2013; 9(4):438–444. DOI:10.1016/j.jalz.2013.03.007 · 17.47 Impact Factor
  • Ezio Giacobini
    Neurobiology of Aging 05/2012; 33:S13-S14. DOI:10.1016/j.neurobiolaging.2012.01.048 · 4.85 Impact Factor
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    ABSTRACT: To gather preliminary evidence in Alzheimer's disease (AD) for the efficacy of phenserine, a non-competitive acetylcholinesterase inhibitor that has independent modulatory effects on amyloid-β generation, a 12-week comparison of patients receiving phenserine (10 and 15 mg BID) or placebo was conducted under double-blind conditions. Patients who completed 12 weeks of the double-blind before others were continued in the double-blind to determine longer-term treatment effects. At 12 weeks, mean ADAS-cog (AD assessment scale-cognitive) changes from baseline were -2.5 and -1.9 for high-dose phenserine (n=83) and placebo (n=81) groups, respectively, a non-statistically significant improvement for the high-dose phenserine group relative to placebo. CIBIC+ (clinician's interview based impression of change + caregiver's input) values for the high-dose and placebo groups were similar at 12 weeks. For patients who received more than 12 weeks of therapy, the ADAS-cog changes were -3.18 and -0.66 for the high-dose phenserine (n=52) and placebo (n=63) groups, respectively, a difference achieving statistical significance (p=0.0286). After 12 weeks, CIBIC+ values were 3.59 and 3.95 for the high-dose (n=54) and placebo (n=66) groups respectively (p=0.0568). These results from this short-term study are consistent with phenserine potentially benefiting mild to moderate Alzheimer's disease symptomatically but do not address possible amyloid metabolic mediated effects on disease processes in AD.
    Journal of Alzheimer's disease: JAD 10/2010; 22(4):1201-8. DOI:10.3233/JAD-2010-101311 · 4.15 Impact Factor
  • Source
    Ana Martínez · Debomoy K Lahiri · Ezio Giacobini · Nigel H Greig
    [Show abstract] [Hide abstract]
    ABSTRACT: Although significant accomplishments have been made in research to understand, diagnose and treat Alzheimer's disease (AD) and its prequel, mild cognitive impairment, over the last two decades, a huge amount more remains to be achieved to impact this incurable, terminal disease that afflicts an estimated 26.6 million people worldwide. Increasing evidence indicates that early diagnosis will be fundamental to maximizing treatment benefits. Moreover, mechanistically-based, hypothesis-driven treatment strategies are now emerging to hopefully spearhead future therapy. The crossfertilization of ideas from multiple disciplines will prove key to optimize strategies and translate them to meaningful clinical utility, and forms the basis of the current issue focused on "Advances in Alzheimer therapy".
    Current Alzheimer research 05/2009; 6(2):83-5. · 3.80 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although significant accomplishments have been made in research to understand, diagnose and treat Alzheimer's disease (AD) and its prequel, mild cognitive impairment, over the last two decades, a huge amount more remains to be achieved to impact this incurable, terminal disease that afflicts an estimated 26.6 million people worldwide. Increasing evidence indicates that early diagnosis will be fundamental to maximizing treatment benefits. Moreover, mechanistically- based, hypothesis-driven treatment strategies are now emerging to hopefully spearhead future therapy. The crossfertilization of ideas from multiple disciplines will prove key to optimize strategies and translate them to meaningful clinical utility, and forms the basis of the current issue focused on “Advances in Alzheimer therapy”.
    Current Alzheimer Research 03/2009; 6(2):83-85. DOI:10.2174/156720509787602924 · 3.80 Impact Factor
  • Source
    Ana Martínez · Debomoy K Lahiri · Ezio Giacobini · Nigel H Greig
    [Show abstract] [Hide abstract]
    ABSTRACT: Although significant accomplishments have been made in research to understand, diagnose and treat Alz-heimer's disease (AD) and its prequel, mild cognitive impairment, over the last two decades, a huge amount more remains to be achieved to impact this incurable, terminal disease that afflicts an estimated 26.6 million people worldwide. Increas-ing evidence indicates that early diagnosis will be fundamental to maximizing treatment benefits. Moreover, mechanisti-cally-based, hypothesis-driven treatment strategies are now emerging to hopefully spearhead future therapy. The cross-fertilization of ideas from multiple disciplines will prove key to optimize strategies and translate them to meaningful clini-cal utility, and forms the basis of the current issue focused on "Advances in Alzheimer therapy". The 10th International Hong Kong/Springfield Pan-Asian Symposium on Advances in Alzheimer Therapy, held in Kowloon, Hong Kong, on February 28, 29 and March 1, 2008, for the first time integrated across East and West more than 1200 basic and clinical research scientists/physicians to impart the latest information to unravel the origin and patho-genesis of Alzheimer's disease (AD) and to both discuss and highlight improvements towards its diagnosis and potential treatment by established as well as novel strategies. This unique biennial symposium series continues to provide a priceless mechanism to bring under the same roof a dichot-omy of scientific interests and expertise to specifically focus them on AD and related dementias and to disseminate the most current knowledge on recent advances in its potential therapy. AD is now recognized as an incurable, degenerative and terminal disease that is global – afflicting an estimated 26.6 million people worldwide in 2006, with the number growing in an unabated and frightening manner.
  • Source
    Robert E Becker · Nigel H Greig · Ezio Giacobini
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) drug developments and clinical trials (CT) remain vulnerable to problems that undermine research validity. Investigations of CT methods reveal how numerous factors decrease active drug-placebo group differences and increase variance, thereby reducing power to reach statistical significance for outcome measure differences in AD CTs. Such factors include, amongst many, inaccuracy, imprecision, bias, failures to follow or lack of operational protocols for applying CT methods, inter-site variance, and lack of homogeneous sampling using disorder criteria. After a review of the literature and survey of a sample of AD and Mild Cognitive Impairment (MCI) CTs, the authors question whether problems of human error preclude AD researchers from continuing their dependence on rated outcome measures for CTs. The authors propose that the realities of AD, especially a probable irreversible progression of neuropathology prior to onset of clinical symptoms or signs capable of differentiating persons at risk for AD from normal aged, require AD investigators and clinicians to privilege biomarkers and encourage their development as surrogate targets for preventive AD treatment developments, testing, and use in clinical practice.
    Journal of Alzheimer's disease: JAD 12/2008; 15(2):303-25. · 3.61 Impact Factor
  • Source
    Ezio Giacobini · Robert E Becker
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    ABSTRACT: Following the introduction of cholinesterase inhibitors in 1986 and a 20-yr long period of successful clinical application in mild, moderate and severe patients, the treatment of AD has turned to modify the course of pathological processes thought to comprise the disease. Several active and passive vaccines are presently under investigation for efficacy, reducing amyloid-beta in the brain of patients with mild-moderately advanced disease. Three large international immunization trials are in progress in US and Europe on mild-moderate AD patients. Among these, the most advanced trial in time is the humanized antibody trial. In addition, drugs aiming to reduce tau phosphorylation (GSK3 inhibitors) are about to enter clinical phases of development. Due to intrinsic difficulties, the developments of gamma-and beta-secretase inhibitors have not yet reached clinical stages. Only one anti-amyloid-aggregation, an aminoglycan compound, and one anti-APO-E approach with rosiglitazone are currently in clinical testing. Stem-cell therapy and gene-replacing therapy remain experimental and far from clinical application. Based on experimental evidence that NGF (nerve growth factor) treatment could provide prolonged protection of the central cholinergic system, i.c.v. infusion of NGF, with genetically modified fibroblasts or gene therapy are under current investigation. NGF treatment could probably double the clinical effect of ChEIs in time. Given the level of scientific and clinical activity it is reasonable to expect that within the next five to ten years a new therapy for AD will, by blocking disease progression, both produce long term stabilization of at least 5 years in patients with AD and prevent or delay emergence in persons at risk for AD.
    Journal of Alzheimer's disease: JAD 09/2007; 12(1):37-52. · 3.61 Impact Factor
  • Nigel H. Greig · Ezio Giacobini · Debomoy K. Lahiri
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    ABSTRACT: Full text available
    Current Alzheimer Research 08/2007; 4(4):336-339. DOI:10.2174/156720507781788819 · 3.80 Impact Factor
  • Article: P3-459

Publication Stats

5k Citations
774.19 Total Impact Points

Institutions

  • 1997–2015
    • University of Geneva
      • • Division of Geriatrics
      • • Department of Rehabilitation and Geriatrics
      Genève, Geneva, Switzerland
  • 2005
    • Hôpitaux Universitaires de Genève
      Genève, Geneva, Switzerland
  • 1984–1996
    • University of Illinois Springfield
      Спрингфилд, Florida, United States
    • Southern Illinois University School of Medicine
      • Department of Pharmacology
      Springfield, IL, United States
  • 1991
    • Tokyo University of Science
      Edo, Tōkyō, Japan
  • 1987
    • Southern Illinois University Carbondale
      • Department of Pharmacology
      Illinois, United States
  • 1985
    • University of Padova
      Padua, Veneto, Italy
  • 1973–1983
    • University of Connecticut
      Storrs, Connecticut, United States
    • University of Helsinki
      • Department of Medical Chemistry
      Helsinki, Uusimaa, Finland
  • 1971
    • University of Minnesota Twin Cities
      Minneapolis, Minnesota, United States
  • 1956–1971
    • Karolinska Institutet
      • Department of Neurobiology, Care Sciences and Society - NVS
      Solna, Stockholm, Sweden
  • 1970
    • Università degli Studi di Torino
      Torino, Piedmont, Italy