Alzheimer Disease: Giacobini E

Martínez A, Lahiri DK, Giacobini E, Greig NH. · No affiliation provided · Curr Alzheimer Res. · Pubmed #19355842 No free full text.

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".

Greig NH, Giacobini E, Lahiri DK. · No affiliation provided · Curr Alzheimer Res. · Pubmed #17908034 No free full text.

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Greig NH, Lahiri DK, Giacobini E. · No affiliation provided · Curr Alzheimer Res. · Pubmed #15974892 No free full text.

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Becker RE, Greig NH, Giacobini E. · Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. · J Alzheimers Dis. · Pubmed #18953116 No free full text.

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.

Giacobini E, Becker RE. · Department of Rehabilitation and Geriatrics, University of Geneva Medical School, Geneva, Switzerland. · J Alzheimers Dis. · Pubmed #17851193 No free full text.

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.

Giacobini E. · Department of Geriatrics, University of Geneva Medical School, University Hospitals of Geneva, CH-1226 Thônex-Geneva, Switzerland. · Pharmacol Res. · Pubmed #15304240 No free full text.

Abstract: An important aspect of brain cholinesterase function is related to enzymatic differences. The brain of mammals contains two major forms of cholinesterases: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally and for their kinetics. Butyrylcholine is not a physiological substrate in mammalian brain which makes the function of BuChE of difficult interpretation. In human brain, BuChE is found in neurons and glial cells as well as in neuritic plaques and tangles in Alzheimer disease (AD) patients. While AChE activity decreases progressively in the brain of AD patients, BuChE activity shows some increase. In order to study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor and found that extracellular acetylcholine increased 15 fold from 5 to 75nM concentrations with little cholinergic side effects in the animal. Based on these data and on clinical data showing a relation between CSF BuChE inhibition and cognitive function in AD patients, we postulated that two pools of cholinesterases may be present in brain, the first mainly neuronal and AChE dependent and the second mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of ACh concentration in brain and can be separated with selective inhibitors. Within particular conditions, such as in mice nullizygote for AChE or in AD patients at advanced stages of the disease, BuChE may replace AChE in hydrolyzing brain acetylcholine. Based on the changes of ChE activity in the brain of AD patients, a rational indication of selective BuChEI (or of mixed double function inhibitors) is the treatment of advanced cases. A second novel aspect of ChEI therapy is the emerging of new indications which include various forms of dementia such as dementia with Lewy Bodies, Down Syndrome, vascular dementia and Parkinson Dementia. Clinical results demonstrate examples of versatility of cholinergic enhancement.

Giacobini E. · Hôpital Universitaire de Geriatrie, Route de Mon Idée, CH-1226 Thônex, Genève, Switzerland. · Int J Geriatr Psychiatry. · Pubmed #12973744 No free full text.

Abstract: Deficits in cholinergic function contribute to the pathology of Alzheimer's disease (AD), affecting cognition, behaviour and activities of daily living. Pharmacological intervention directed towards these deficits is based on acetylcholinesterase (AChE) inhibition. Whether such drugs have reached their therapeutic 'ceiling' is an open question and it is possible that cholinergic intervention may be usefully combined with other therapeutic mechanisms. Data relating to such issues are still being collected. In severe AD, levels of AChE and choline acetyltransferase are decreased by as much as 90% compared with normal, whilst butyrylcholinesterase (BuChE) increases. In such instances, it is possible that BuChE may be a more appropriate therapeutic target. Both AChE and BuChE are aggregated in senile plaques along with beta-amyloid, and investigations are being undertaken to determine whether drugs can be developed that inhibit AChE whilst also acting on beta-amyloid. Deficits in nicotinic binding sites have led to hopes for new nicotinic drugs. Cholinergic therapies can potentially cause unwanted side effects and the search for the 'ideal' inhibitor continues. Combinations of drugs may ultimately prove to be the most productive means of treating patients with AD.

Giacobini E. · University Hospitals of Geneva, Department of Geriatrics, University of Geneva, Medical school. CH-1226 Thônex, Geneva, Switzerland. · Neurochem Res. · Pubmed #12675140 No free full text.

Abstract: The most important therapeutic effect of cholinesterase inhibitors (ChEI) on approximately 50% of Alzheimer's disease (AD) patients is to stabilize cognitive function at a steady level during a 1-year period of treatment as compared to placebo. Recent studies show that in a certain percentage (approximately 20%) of patients this cognitive stabilizing effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic and cholinergic. In vitro and in vivo studies have consistently demonstrated a link between cholinergic activation and APP metabolism. Lesions of cholinergic nuclei cause a rapid increase in cortical APP and CSF. The effect of such lesions can be reversed by ChEI treatment. Reduction in cholinergic neurotransmission--experimental or pathological, such as in AD--leads to amyloidogenic metabolism and contributes to the neuropathology and cognitive dysfunction. To explain the long-term effect of ChEI, mechanisms based on beta-amyloid metabolism are postulated. Recent data show that this mechanism may not necessarily be related to cholinesterase inhibition. A second important aspect of brain cholinesterase function is related to enzymatic differences. The brain of mammals contains two major forms of cholinesterases: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally, and for their kinetics. Butyrylcholine is not a physiological substrate in mammalian brain, which makes the function of BuChE of difficult interpretation. In human brain, BuChE is found in neurons and glial cells, as well as in neuritic plaques and tangles in AD patients. Whereas, AChE activity decreases progressively in the brain of AD patients, BuChE activity shows some increase. To study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor and found that extracellular acetylcholine increased 15-fold from 5 nM to 75 nM concentrations with little cholinergic side effect in the animal. Based on these data and on clinical data showing a relation between cerebrospinal fluid (CSF) BuChE inhibition and cognitive function in AD patients, we postulated that two pools of cholinesterases may be present in brain, the first mainly neuronal and AChE dependent and the second mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of ACh concentration in brain and can be separated with selective inhibitors. Within particular conditions, such as in mice nullizygote for AChE or in AD patients at advanced stages of the disease, BuChE may replace AChE in hydrolizing brain acetylcholine.

Lahiri DK, Farlow MR, Sambamurti K, Greig NH, Giacobini E, Schneider LS. · Department of Psychiatry and Neurology, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202-4887, USA. · Curr Drug Targets. · Pubmed #12558063 No free full text.

Abstract: Alzheimer's disease (AD), a progressive, degenerative disorder of the brain, is believed to be the most common cause of dementia amongst the elderly. AD is characterized by the presence of amyloid deposits and neurofibrillary tangles in the brain of afflicted individuals. AD is associated with a loss of the presynaptic markers of the cholinergic system in the brain areas related to memory and learning. AD appears to have a heterogeneous etiology with a large percentage termed sporadic AD arising from unknown causes and a smaller fraction of early onset familial AD (FAD) caused by mutations in one of several genes, such as the beta-amyloid precursor protein (APP) and presenilins (PS1, PS2). These proteins along with tau, secretases, such as beta-amyloid cleaving enzyme (BACE), and apolipoprotein E play important roles in the pathology of AD. On therapeutic fronts, there is significant research underway in the development of new inhibitors for BACE, PS-1 and gamma-secretase as targets for treatment of AD. There is also a remarkable advancement in understanding the function of cholinesterase (ChE) in the brain and the use of ChE-inhibitors in AD. A new generation of acetyl- and butyryl cholinesterase inhibitors is being studied and tested in human clinical trials for AD. The development of vaccination strategies, anti-inflammatory agents, cholesterol-lowering agents, anti-oxidants and hormone therapy are examples of new approaches for treating or slowing the progression of AD. In addition, nutritional, genetic and environmental factors highlight more effective preventive strategies for AD. Developments of early diagnostic tools and of quantitative markers are critical to better follow the course of the disease and to evaluate different therapeutic strategies. In this review, we attempt to critically examine recent trends in AD research from molecular, genetic to clinical areas. We discuss various neurobiological mechanisms that provide the basis of new targets for AD drug development. All these current research efforts should lead to a deeper understanding of the pathobiochemical processes that occur in the AD brain in order to effectively diagnose and prevent their occurrence.

Giacobini E. · Department of Geriatrics, University Hospitals of Geneva, University of Geneva, Medical School, Thonex, Geneva, Switzerland. · J Neural Transm Suppl. · Pubmed #12456062 No free full text.

Abstract: During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer disease (AD) resulted into three drugs being registered for the first time in USA and Europe. All three compounds are cholinesterase inhibitors (ChEI). The major therapeutic effect of ChEI on AD patients is to maintain cognitive function at a stable level during a 6 months to one year period of treatment as compared to placebo. Additional drug effects are slowing cognitive deterioration and improving behavioral and daily living activity. Recent studies show that in many patients the cognitive stabilization effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic and direct cholinergic. In vitro and in vivo studies have consistently demonstrated a link between cholinergic activation and APP metabolism. Lesions of cholinergic nuclei cause a rapid increase in cortical APP and CSF. The effect of such lesions can be reversed by ChEI treatment. Reduction in cholinergic neurotransmission experimental or pathological (AD) leads to amyloidogenic metabolism and contributes to the neuropathology and cognitive dysfunction. In order to explain the long-term effect of ChEI, a mechanism based on beta-amyloid metabolism, is postulated. Evidence for such an effect is available at experimental as well as at clinical level. Does cholinergic stabilization imply slowing down disability or delaying disease progression?

Giacobini E. · Department of Geriatrics, School of Medicine, University Hospitals of Geriatrics, University of Geneva, Geneva, Switzerland. · Drugs Aging. · Pubmed #11888344 No free full text.

Abstract: The brain of mammals contains two major forms of cholinesterases (ChEs): acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally and in their kinetics. Butyrylcholine is not a physiological substrate in mammalian brains which makes the function of BuChE difficult to interpret. In human brains, BuChE is found in neurons and glial cells as well as in neuritic plaques and tangles in patients with Alzheimer's disease (AD).While AChE activity decreases progressively in the brain of patients with AD, BuChE activity shows some increase. In order to study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor. We found that extracellular acetylcholine levels increased 15-fold from 5 nmol/L to 75 nmol/L concentrations, with little cholinergic adverse effect in the animal. Based on these data, we postulated that two pools of ChEs may be present in the brain: one mainly neuronal and AChE dependent; and one mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of acetylcholine concentration in the brain and can be separated with selective inhibitors. The recent development of highly selective BuChE inhibitors will allow us to test these new agents in patients with AD in order to find out whether or not they represent an advantage for the treatment of patients with AD as compared with selective (donepezil) or relatively non-selective (rivastigmine, galantamine) ChE inhibitors presently in use. The association between a BuChE-K variant and AD has not been confirmed in several studies. In conclusion, additional experimental and clinical work is necessary in order to elucidate the role of BuChE in normal brain function and in the brains of patients with AD. In the future, it may be possible that selective BuChE inhibitors will have a role in treatment of patients with advanced AD.

Giacobini E. · University Hospitals of Geneva, Department of Geriatrics, University of Geneva Medical School, Thonex, Switzerland. · CNS Drugs. · Pubmed #11460892 No free full text.

Abstract: During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer disease (AD) has resulted in drugs being registered for the first time in the US and Europe for this specific indication. The 3 agents registered are cholinesterase inhibitors (ChEIs). The major therapeutic effect of ChEIs in patients with AD is the maintenance of cognitive function, as compared with placebo, during a 6-month to 1-year period of treatment. Additional drug effects that may occur are the slowing of cognitive deterioration and improvement of behaviour and daily living activities. Comparison of clinical effects of 6 ChEIs demonstrates a rather similar magnitude of improvement in cognitive outcome measures. For some drugs, this level may represent an upper limit, while for others it may be possible to increase the benefit further. In order to maximise and prolong positive drug effects it is important to start treatment early and adjust the dosage during treatment. Recent studies that used this administration strategy have shown that in many patients, the stabilisation effect produced by ChEIs can be prolonged for as long as 36 months. This long-lasting effect suggests mechanisms of action other than symptomatic ones. In this article, the effects of ChEIs on beta-amyloid metabolism are postulated to explain the stabilising (i.e. disease-modifying) effects of the drugs. Evidence for such a mechanism is available at the experimental but not yet at the clinical level.

Michel JP, Zekry D, Mulligan R, Giacobini E, Gold G. · Department of Geriatrics, Geneva University Hospitals, Switzerland. · Aging (Milano). · Pubmed #11442307 No free full text.

Abstract: Economic analyses of geriatric syndromes are seldom performed. However, demographic and epidemiological imperatives have led to significant interest in the evaluation of AD-related costs. Over 300 papers devoted to economic considerations of Alzheimer's disease have been published in peer-reviewed journals, within the last five years. In these papers, the chosen perspective (costs to society or to specific payers) is important. Analytical methods are still evolving and remain complex. Unresolved methodological issues will need to be addressed to further our understanding of long-term economic consequences. At present, it is clear that diagnostic and drug costs are low compared to the major cost of institutionalization. Thus, directing efforts at early diagnosis and delaying nursing home placement are two key cost-containment interventions. In this respect, the need to support informal care should not be underestimated.

Giacobini E. · University Hospitals of Geneva, Department of Geriatrics, University of Geneva Medical School, Thonex-Geneva, Switzerland. · Aging (Milano). · Pubmed #11442306 No free full text.

Abstract: During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer's disease (AD) resulted in three drugs being registered for the first time in the US and Europe. All three compounds are cholinesterase inhibitors (ChEI). The major therapeutic effect of ChEI on AD patients is to maintain cognitive function at a stable level during a 6-month to 1-year period of treatment, as compared to placebo. Additional drug effects are to slow down cognitive deterioration and improve behavioral and daily living activity. Recent studies show that in many patients the cognitive stabilization effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic, and directly cholinergic. In vitro and in vivo studies have consistently demonstrated a link between cholinergic activation and amyloid precursor protein (APP) metabolism. Lesions of cholinergic nuclei cause a rapid increase in cortical APP and cholinergic synaptic function; the effect of such lesions can be reversed by ChEI treatment. A reduction in cholinergic neurotransmission, experimental or pathological, leads to amyloidogenic metabolism and contributes to the development of neuropathology and cognitive dysfunction. To explain the long-term effect of ChEI, for which evidence is available on an experimental as well as clinical level, a mechanism based on beta-amyloid metabolism is postulated. The question whether cholinergic stabilization implies simply slowing down progression of disability or also involves delay of disease progression is discussed.

Giacobini E. · University Hospitals of Geneva, Department of Geriatrics, University of Geneva, Medical School, CH-1226 Thonex, Geneva, Switzerland. · Ann N Y Acad Sci. · Pubmed #11193171 No free full text.

Abstract: During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer disease (AD) has resulted into three drugs being registered for the first time in the USA and Europe for this specific indication. All three are cholinesterase inhibitors (ChEI). The major therapeutic effect of ChEI on AD patients is to maintain cognitive function at a constant level during a six-month to one-year period of treatment, as compared to placebo. Additional drug effects might slow cognitive deterioration and improve behavioral and daily living conditions. Comparison of clinical effects of six ChEI demonstrates a rather similar magnitude of improvement in cognitive measures. For some drugs, this may represent an upper limit, whereas for other it may still be possible to further increase the benefit. In order to maximize and prolong positive drug effects, it is important to start early and adjust dosage during the treatment. Recent studies show that in many patients the stabilization effect produced by ChEI can be prolonged for as long as a 24-month period. In order to explain the stabilizing effect of ChEI, a mechanism other than AChE inhibition, based on beta-amyloid metabolism, is postulated.

Giacobini E. · University Hospitals of Geneva, Department of Geriatrics, University of Geneva, Medical School, Thonex, Switzerland. · Neurochem Res. · Pubmed #11059792 No free full text.

Abstract: During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer disease (AD) has resulted into three drugs being registered for the first time in USA and Europe for this specific indication. All three are cholinesterase inhibitors (ChEI). The major therapeutic effect of ChEI on AD patients is to maintain cognitive function at a constant level during a 6 months to one year period of treatment as compared to placebo. Additional drug effects might be slowing cognitive deterioration and improving behavioral and daily living conditions. Comparison of clinical effects of 6 ChEI demonstrates a rather similar magnitude of improvement in cognitive measures. For some drugs. this may represent an upper limit while for other it may still be possible to increase further the benefit. In order to maximize and prolong positive drug effects it is important to start early and adjust dosage during the treatment. Recent studies show that in many patients the stabilization effect produced by ChEI can be prolonged for as long as a 24 month period. In order to explain the stabilizing effect of ChEI, a mechanism other than AChE inhibition, based on beta-amyloid metabolism, is postulated.

Giacobini E. · Department of Geriatrics, University Hospitals of Geneva, Medical School, Thônex-Geneva, Switzerland. · J Neural Transm Suppl. · Pubmed #10961434 No free full text.

Abstract: Three major lines of drugs have been developed or are under development for the treatment of Alzheimer Disease (AD): cholinergic drugs (mainly cholinesterase inhibitors), anti-beta-amyloid drugs, estrogens and anti-inflammatories. Cholinesterase inhibitors are the only drugs presently approved in USA and Europe for the indication of AD. Cholinesterase inhibitors tested in clinical trials in Europe, USA and Japan include less than ten drugs, however most of these compounds have advanced to clinical trials III. Based on results related to a population of over 8,000 patients we conclude that several of these compounds have shown significant clinical efficacy and safety in the treatment of Alzheimer disease. There are, however, differences with regard to side effects. The major clinical effect is stabilization of cognitive function during a six- to 12-months period with a parallel improvement of behavioral symptoms. Long-term effect of cholinesterase inhibitors extending to a two year-period has been reported. Future applications of these drugs are treatment of other types dementias such as Lewy body dementia, vascular dementia and Down Syndrome dementia. Combination of cholinesterase inhibitors with estrogens, anti-oxidants and anti-inflammatories may represent a further improvement of the therapy. From the economical point of view, treatment with cholinesterase inhibitors is not cost neutral.

Giacobini E. · Department of Geriatrics, University Hospitals of Geneva, University of Geneva Medical School, Switzerland. · Alzheimer Dis Assoc Disord. · Pubmed #10850724 No free full text.

Abstract: Cholinesterase inhibitors tested in clinical trials in Europe, the United States, and Japan include fewer than 10 drugs; however, most of these compounds have advanced to clinical phase III trials. Based on results related to a population of more than 8,000 patients, we conclude that several of these compounds have shown significant clinical efficacy and safety in the treatment of Alzheimer disease. There are, however, differences with regard to side effects. The major clinical effect is stabilization of cognitive function during a 6- to 12-month period with an improvement of behavioral symptoms. The long-term effect of cholinesterase inhibitors extending to a 2-year period was reported. Future applications of these drugs include treatment of other types of dementias such as Lewy bodies dementia, vascular dementia, and Down syndrome dementia. The combination of cholinesterase inhibitors with estrogens, antioxidants, and anti-inflammatories may represent a further improvement of the therapy. From an economical point of view, treatment with cholinesterase inhibitors is not cost neutral.

Giacobini E, Spiegel R, Enz A, Veroff AE, Cutler NR. · Institutions Universitaires de Geriatrie de Geneve, Route de Mon-Idēe, CH-1226 Thonex-Geneva, Switzerland. · J Neural Transm. · Pubmed #12111443 No free full text.

Abstract: Cholinesterase (ChE) inhibition represents the most efficacious treatment approach for Alzheimer's disease (AD) to date. This multiple-dose study has examined the relationship between inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities in the cerebrospinal fluid (CSF) and cognitive change (measured by the Computerised Neuropsychological Test Battery [CNTB]) following administration of the ChE inhibitor, rivastigmine (Exelon). In 18 patients with mild to moderate AD, CNTB scores, activities of AChE and BuChE in the CSF, and plasma BuChE activity were determined prior to treatment with rivastigmine. Doses of rivastigmine were then titrated (1 mg b.i.d./week) to final doses of 1, 2, 3, 4, 5 or 6 mg b.i.d. (n = 3 per dose). Following treatment with the target dose of rivastigmine for at least 3 days, CNTB scores were re-determined. CSF samples were continuously collected together with plasma samples prior to and for 12 hours after the final dose of rivastigmine, and AChE and BuChE activities determined.AChE in CSF and BuChE in plasma were dose-dependently inhibited by rivastigmine treatment. The inhibition of BuChE in CSF was not clearly dose-dependent. A statistically significant correlation was observed between the change in CNTB summary score and inhibition of AChE activity (r = -0.56, p < 0.05) and BuChE activity (r = -0.65, p < 0.01) in CSF. Improvement in speed-, attention- and memory-related subtests of the CNTB correlated significantly with inhibition of BuChE but not AChE activity in CSF. Weak or absent correlation with change in cognitive performance was noted for inhibition of plasma BuChE. These results indicate that cognitive improvement with rivastigmine in AD is associated with central inhibition of ChEs and support a role for central BuChE in addition to AChE inhibition in modulating cholinergic function in AD.

Du Pasquier R, Cavassini M, Simioni S, Annoni JM, Giacobini E, Hirschel B. · Service de Neurologie, CHUV, Lausanne. · Rev Med Suisse. · Pubmed #19476058 No free full text.

Abstract: Highly active anti-retroviral therapy (HAART) has almost abolished HIV-related mortality and serious opportunistic diseases; among them, AIDS-related dementia. However, minor forms of cognitive dysfunction, have not disappeared, and even increased in frequency. Ageing of HIV+ patients, insufficient penetration of anti-viral drugs into the brain with continuous low-grade viral production and inflammation may play a role. Minor cognitive dysfunction in HIV infection shares some clinical and pathophysiological features with neuro-degenerative diseases, in particular Alzheimers disease. It can thus be postulated that, such in Alzheimer disease, anti-cholinesterase drugs might also be efficacious in AIDS-related minor cognitive dysfunction. This hypothesis has not been tested yet however A clinical trial using ravistigmine is starting this spring in patients with HIV-associated cognitive dysfunction in Geneva and Lausanne.

Onder G, Zanetti O, Giacobini E, Frisoni GB, Bartorelli L, Carbone G, Lambertucci P, Silveri MC, Bernabei R. · Department of Gerontology, Geriatrics and Psychiatry, Catholic University, Rome. · Br J Psychiatry. · Pubmed #16260821 links to  free full text

Abstract: BACKGROUND: Reality orientation therapy combined with cholinesterase inhibitors has not been evaluated in patients with Alzheimer's disease. AIMS: To perform such an evaluation. METHOD: We randomly assigned 79 of 156 patients treated with donepezil to receive a reality orientation programme. Caregivers of the treatment group were trained to offer the programme at home 3 days a week, 30 min/day, for 25 consecutive weeks, and were invited to stimulate and involve patients in reality-based communication. RESULTS: The treatment group showed a slight improvement in Mini-Mental State Examination (MMSE) scores (mean change +0.2, s.e.=0.4) compared with a decline in the control group (mean change -1.1, s.e.=0.4; P=0.02). Similarly for the Alzheimer's Disease Assessment Scale--Cognition (treatment group mean change +0.4, s.e.=0.8; control group -2.5, s.e.=0.8; P=0.01). The intervention had an equal effect on cognition in those with mild (MMSE score > or = 20) and moderate (score <20) dementia. No significant effect was observed for behavioural and functional outcomes. CONCLUSIONS: Reality orientation enhances the effects of donepezil on cognition in Alzheimer's disease.

Slosman DO, Ludwig C, Zerarka S, Pellerin L, Chicherio C, de Ribaupierre A, Annoni JM, Bouras C, Herrmann F, Michel JP, Giacobini E, Magistretti PJ. · Division of Nuclear Medicine, Geneva University Hospital, Geneva, Switzerland. · Brain Res Brain Res Rev. · Pubmed #11690620 No free full text.

Abstract: The central hypothesis of the study which has been carried out as part of the NRP38 program, is that perturbations of brain energy metabolism are critically involved in the neurodegeneration occurring in Alzheimer's disease (AD) and that they may correlate with early cognitive dysfunctioning. In the present multidisciplinary study we set out to monitor brain energy metabolism using FDG-PET and HMPAO-SPECT imaging in a cohort of individuals over 65 years of age, drawn from the general population. HMPAO-SPECT imaging, which is a simpler and more widely accessible imaging procedure than FDG-PET, was performed under basal conditions and during the performance of a cognitive task (verbal fluency test). Three groups were studied. Two groups (groups I and II) included individuals age 65 or more, with no cognitive impairment and carrying an APOE4 positive or APOE4 negative phenotype, respectively; a third group (group III) included patients with clinical signs of AD. Each subject entering the study underwent an FDG-PET, an HMPAO-SPECT and an extensive battery of neuropsychological tests which assess various aspects of cognitive functioning, with a strong emphasis on working memory, divided attention and executive functions. A total of 101 participants were submitted to brain imaging and neuropsychological testing. Among these, 60 participants received the same set of imaging and neuropsychological tasks 24-36 months after the first set (phase II). In this article, we present a preliminary analysis performed on ten subjects from groups I and II and nine subjects from group III: activation (verbal fluency task) induced a specific pattern of increase in HMPAO retention (including BA 9/10, BA 18 bilaterally and right BA 17). In contrast to controls, in nine AD subjects no significant differences in HMPAO retention were observed when comparing activation and basal conditions. The cellular and molecular mechanisms that underlie the retention of HMPAO, the tracer used for single photon emission computed tomography (SPECT) imaging, has been studied in vitro in purified preparations of neurons and astrocytes with the aim of investigating the contribution of different cell types to hexamethyl-propyleneamineoxime labeled with technetium-99m (99mTc-HMPAO) retention in vitro. Results show that 99mTc-HMPAO retention predominates in astrocytes over neurons by a factor of approximately 2.5. Diethyl maleate, ethacrynic acid and buthionine sulfoximine, three agents which significantly reduce glutathione levels, also decreased 99mTc-HMPAO retention in both astrocytes and in neurons. Decrease did not always correlate with glutathione levels however, thus suggesting that other factors could be involved. The data presented indicate that astrocytes might constitute a prominent site of 99mTc-HMPAO retention and most likely contribute significantly to the SPECT signal. In addition, they also suggest that specific alterations in glial cell metabolism could explain flow-independent changes in 99mTc-HMPAO retention in the brain as observed by SPECT in certain pathologies (including Alzheimer's disease). In particular, these observations suggest a key role of astrocytes in the signal detected with the imaging procedure, which is altered in the Alzheimer's cohort subjected to the verbal fluency activation task.

Wevers A, Monteggia L, Nowacki S, Bloch W, Schütz U, Lindstrom J, Pereira EF, Eisenberg H, Giacobini E, de Vos RA, Steur EN, Maelicke A, Albuquerque EX, Schröder H. · Department of Anatomy, University of Köln, Joseph-Stelzmann Strasse 9, 50931 Köln, Germany. · Eur J Neurosci. · Pubmed #10383644 No free full text.

Abstract: Impairment of cholinergic transmission and decreased numbers of nicotinic binding sites are well-known features accompanying the cognitive dysfunction seen in Alzheimer's disease (AD). In order to elucidate the underlying cause of this cholinoceptive dysfunction, the expression of two pharmacologically different nicotinic acetylcholine receptor (nAChR) subunits (alpha4, alpha7) was studied in the cerebral cortex of Alzheimer patients as compared to controls. Patch-clamp recordings of 14 dissociated neurons of control cortices showed responses suggesting the existence of alpha4- and alpha7-containing functional nAChRs in the human cortex. In cortices of Alzheimer patients and controls, the pattern of distribution and the number of alpha4 and alpha7 mRNA-expressing neurons were similar, whereas at the protein level a decrease in the density of alpha4- and alpha7-expressing neurons of approximately 30% was observed in Alzheimer patients. The histotopographical correlation of nAChR expression with accompanying pathological changes, e.g. accumulation of hyperphosphorylated-tau (HP-tau) protein and beta-amyloid showed that neurons in the vicinity of beta-amyloid plaques bore both nAChR transcripts. Neurons heavily labelled for HP-tau, however, expressed little or no alpha4 and alpha7 mRNA. These results point to an impaired synthesis of nAChRs on the protein level as a possible cause of the cholinoceptive deficit in AD. Further investigations need to elucidate whether interactions of HP-tau with nAChR mRNA, or alterations in the quality of alpha4 and alpha7 transcripts give rise to decreased protein expression at the level of individual neurons.