Alzheimer Disease: Gauthier S

Vellas B, Gauthier S, Allain H, Andrieu S, Aquino JP, Berrut G, Berthel M, Blanchard F, Camus V, Dartigues JF, Dubois B, Forette F, Franco A, Gonthier R, Grand A, Hervy MP, Jeandel C, Joel ME, Jouanny P, Lebert F, Michot P, Montastruc JL, Nourhashemi F, Ousset PJ, Pariente J, Rigaud AS, Robert P, Ruault G, Strubel D, Touchon J, Verny M, Vetel JM, Anonymous00344. · CHU Casselardit, Toulouse. · Rev Neurol (Paris). · Pubmed #16244574 No free full text.

Abstract: Under the auspices of the French Society of Gerontology and Geriatrics, a multidisciplinary team including geriatritians, neurologists, epidemiologists, psychiatrists, pharmacologists and public health specialists developed a consensus on care for patients with severe dementia. They defined 21 recommendations for general practitioners, long-term care physicians and specialists based on knowledge available in 2005. At all stages of the disease, the objective of care is to improve as much as possible quality-of-life for the patient and his/her family, including a life project until the end of life. It is always possible to do something for these patients and their family: nutritional status, behavior disorders, and incapacities to deal with basic activities of daily life have to be taken in consideration. Resource allocation and proximity care have to be targeted. Research areas necessary to improve the care of patients with severe dementia has been selected.

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Anonymous00346. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #16237129 No free full text.

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Brodaty H, Dresser R, Eisner M, Erkunjuntti T, Gauthier S, Graham N, Jonker C, Sachs G, Whitehouse P. · No affiliation provided · Alzheimer Dis Assoc Disord. · Pubmed #10372949 No free full text.

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Gauthier S, Poirier J. · Department of Neurology and Neurosurgery, and McGill Center for Studies in Aging, McGill University, and Douglas Mental Health University Institute, Montreal, Quebec, Canada. · Alzheimers Dement. · Pubmed #19328447 No free full text.

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Reisberg B, Gauthier S. · No affiliation provided · Int Psychogeriatr. · Pubmed #18072981 No free full text.

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Gauthier S. · No affiliation provided · J Nutr Health Aging. · Pubmed #17066214 No free full text.

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Gauthier S. · No affiliation provided · BMJ. · Pubmed #15831849 links to  free full text

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Whitehouse PJ, Arizaga R, Brodaty H, Gauthier S, Graham N, Green RC, Homma A, Mangone C, Senanarong V, Xu XH. · No affiliation provided · Alzheimer Dis Assoc Disord. · Pubmed #10485568 No free full text.

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Erkinjuntti T, Gauthier S. · Memory Research Unit, Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland. · Front Neurol Neurosci. · Pubmed #19182465 No free full text.

Abstract: Vascular cognitive impairment (VCI) is the modern term related to vascular burden of the brain,reflecting all encompassing effects of cerebrovascular disease (CVD) on cognition. VCI include all levels of cognitive decline from mild deficits in one or more cognitive domains to a broad dementia-like syndrome. VCI incorporates the complex interactions between vascular risk factors, CVD etiologies and cellular changes within the brain and cognition. Vascular risk factors towards VCI include,e.g. arterial hypertension, high cholesterol, and diabetes. VCI includes the common poststroke dementia and vascular dementia (VaD). The main subtypes of VaD include the cortical VaD or multi-infarct dementia also referred as poststroke VaD and subcortical ischemic vascular disease and dementia or small vessel dementia. Traditional vascular risk factors and stroke are also independent factors for the clinical presentation of Alzheimer's disease. In addition to these vascular factors, CVD/strokes, infarcts and white matter lesions may trigger and modify progression of Alzheimer's disease.Whilst CVD is preventable and treatable, it clearly is a major factor in the prevalence of cognitive impairment in the elderly worldwide.

Herrmann N, Gauthier S. · Department of Psychiatry, Sunnybrook Health Sciences Centre and University of Toronto, Ont., Canada. · CMAJ. · Pubmed #19047609 links to  free full text

Abstract: BACKGROUND: The management of severe Alzheimer disease often presents difficult choices for clinicians and families. The disease is characterized by a need for full-time care and assistance with basic activities of daily living. We outline an evidence-based approach for these choices based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. METHODS: We developed evidence-based guidelines using systematic literature searches, with specific criteria for the selection and quality assessment of articles, and a clear and transparent decision-making process. We selected articles published from January 1996 to December 2005 that dealt with the management of severe Alzheimer disease. Subsequent to the conference, we searched for additional articles published from January 2006 to March 2008 using the same search terms. We graded the strength of the evidence using the criteria of the Canadian Task Force on Preventive Health Care. RESULTS: We identified 940 articles, of which 838 were selected for further study. Thirty-four articles were judged to be of at least good or fair quality and were used to generate 17 recommendations. Assessment of severe Alzheimer disease should include the measurement of cognitive function and the assessment of behaviour, function, medical status, nutrition, safety and caregiver status. Management could include treatment with a cholinesterase inhibitor or memantine, or both. Treatment of neuropsychiatric symptoms begins with nonpharmacologic approaches to addressing behavioural problems. Severe agitation, aggression and psychosis, which are potentially dangerous to the patient, the caregiver and others in the environment, can be treated with atypical antipsychotics, with consideration of their increased risk of cerebrovascular events and death. All pharmacologic approaches require careful monitoring and periodic reassessment to determine whether continued treatment is necessary. Caregiver support and use of community resources are essential. INTERPRETATION: Severe Alzheimer disease requires frequent monitoring by health professionals. Simple nonpharmacologic approaches may address problems with mood and agitation. Antipsychotic drug therapy is occasionally necessary despite the inherent risks. Therapy with a cholinesterase inhibitor and memantine may be useful for selected patients.

Gauthier S, Poirier J. · McGill Center for Studies in Aging, Douglas Institute for Mental Health, Montreal, Quebec, Canada. · Alzheimers Dement. · Pubmed #18632000 No free full text.

Abstract: The full span of Alzheimer's disease, from asymptomatic, pre-dementia, mild-to-moderate stages, should be considered in the management. There are multiple research opportunities for better understanding and treatment of this condition. Ongoing cohort studies developed under Leon Thal's leadership will facilitate this process.

Ferreri F, Agbokou C, Gauthier S. · Unité de recherche sur la maladie d'Alzheimer, centre McGill d'études sur le vieillissement, Montréal, Canada. · Rev Neurol (Paris). · Pubmed #18033034 No free full text.

Abstract: INTRODUCTION: In the treatment of mild to moderate Alzheimer's disease, cholinesterase inhibitors (ChEIs) have shown modest clinical benefits. STATE OF THE ART: Use of donepezil, galantamine and rivastigmine is widespread in clinical practice. Although relatively safe, ChEIs are prescribed for a frail population and may have clinically significant adverse drug effects on the cardiovascular system. Arrhythmia and syncope have been reported. Most of the cardiovascular adverse drug reactions to ChEIs might be related to stimulation of the parasympatic nervous system. PERSPECTIVES: Early and accurate recognition of past and present arrhythmia or syncope appears to be essential. Monitoring for pharmacokinetic (cytochromes P450 CYP2D6 or CYP3A4) and pharmacodynamic interactions and a more systematic clinical follow-up are mandatory. In patients with relevant risk factors or with cardiovascular adverse drug reactions a multidisciplinary approach with a cardiologist is required. CONCLUSION: Prevention of cardiac adverse events requires a careful clinical evaluation before the introduction of the ChEIs and an early recognition of cardiac disturbances under treatment.

Seow D, Gauthier S. · Alzheimer Disease Research Unit, McGill Centre for Studies in Aging, Montreal, Quebec. · Can J Psychiatry. · Pubmed #18020110 No free full text.

Abstract: OBJECTIVE: To systematically review published clinical trials of the pharmacotherapy of Alzheimer disease (AD). METHOD: We searched MEDLINE for published English-language medical literature, using Alzheimer disease and treatment as key words. No other search engine was used. Our review focused on randomized clinical trials (RCTs) and corresponding metaanalyses. RESULTS: Although there are many RCTs for the treatment of mild cognitive impairment (MCI), none have been successful in their primary analysis. The cholinesterase inhibitors donepezil, rivastigmine, and galantamine have demonstrated efficacy in 3- to 12-month placebo-controlled RCTs assessing cognitive, functional, behavioural, and global outcomes in patients with mildly to moderately severe AD. Recent data from patients with severe stages of AD demonstrate the efficacy of donepezil on cognitive and functional measures but not on behaviour. The N-methyl-D-aspartate receptor antagonist memantine has been demonstrated to be effective in 6-month, placebo-controlled RCTs of 6 months duration assessing cognitive, functional, and global outcomes of inpatients with moderate-to-severe AD (defined as a Mini Mental State Examination score below 20). Post hoc analyses have demonstrated a benefit in regard to agitation and (or) aggression, but this needs to be confirmed in a prospective RCT across Canada. Disease-modifying treatments are being tested in mild stages of AD in 18-month RCTs with cognitive and global outcomes as primary efficacy outcomes, primarily with drugs reducing amyloid synthesis or aggregation. Successful treatment in mild stages of AD could lead to RCTs in MCI and, possibly, in genetically high-risk asymptomatic individuals. CONCLUSION: The significant advances in the symptomatic pharmacotherapy of AD may be followed by disease-modification treatments.

Aisen PS, Gauthier S, Vellas B, Briand R, Saumier D, Laurin J, Garceau D. · Department of Neurology, Georgetown University, Washington, DC 20057, USA. · Curr Alzheimer Res. · Pubmed #17908052 No free full text.

Abstract: As a potential disease-modifying treatment for AD, Alzhemed (tramiprosate) is a compound that binds to soluble amyloid-beta peptide (Abeta) and inhibits the formation of neurotoxic aggregates that lead to amyloid plaque deposition in the brain. The safety, tolerability, and pharmacodynamic effects of Alzhemed were assessed in a double-blind study in which 58 individuals with mild-to-moderate AD (MMSE 13-25) were randomized to receive placebo or Alzhemed 50, 100 or 150 mg BID for 3 months. At the end of the double-blind phase, 42 of these subjects entered a 36-month open-label (OL) phase in which they received Alzhemed 150 mg BID. Assessments included plasma and cerebrospinal fluid (CSF) Alzhemed concentrations, CSF levels of Abeta, as well as cognitive (Alzheimer's Disease Assessment Scale-cognitive subscale, Mini-Mental State Examination) and clinical performance (Clinical Dementia Rating scale, Sum-of-Boxes) measures. Alzhemed was safe and well tolerated, crossed the blood-brain barrier, and dose-dependently reduced CSF Abeta(42) levels after 3 months of treatment. Mild AD subjects (MMSE 19-25 at entry) displayed greater reduction of CSF Abeta(42) levels than moderate AD participants (MMSE 13-18 at entry). There was no effect of Alzhemed on the cognitive or clinical measures after 3 months of treatment. The OL follow-up suggested a stabilization of cognitive function especially in mild AD subjects over the 36-month study period. Alzhemed thus appears to be well tolerated with long-term exposure and reduces CSF Abeta(42) levels in mild-to-moderate AD subjects. These findings will be discussed in the context of two large-scale randomized, double-blind, placebo-controlled Phase III clinical trials that are currently being conducted to test the long-term safety and efficacy of Alzhemed.

Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. · INSERM U610, Hôpital de la Salpêtrière, Paris, France. · Lancet Neurol. · Pubmed #17616482 No free full text.

Abstract: The NINCDS-ADRDA and the DSM-IV-TR criteria for Alzheimer's disease (AD) are the prevailing diagnostic standards in research; however, they have now fallen behind the unprecedented growth of scientific knowledge. Distinctive and reliable biomarkers of AD are now available through structural MRI, molecular neuroimaging with PET, and cerebrospinal fluid analyses. This progress provides the impetus for our proposal of revised diagnostic criteria for AD. Our framework was developed to capture both the earliest stages, before full-blown dementia, as well as the full spectrum of the illness. These new criteria are centred on a clinical core of early and significant episodic memory impairment. They stipulate that there must also be at least one or more abnormal biomarkers among structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of amyloid beta or tau proteins. The timeliness of these criteria is highlighted by the many drugs in development that are directed at changing pathogenesis, particularly at the production and clearance of amyloid beta as well as at the hyperphosphorylation state of tau. Validation studies in existing and prospective cohorts are needed to advance these criteria and optimise their sensitivity, specificity, and accuracy.

Gauthier S. · Alzheimer Disease Research Unit, McGill Centre for Studies in Aging, Verdun, Quebec, Canada. · Can J Neurol Sci. · Pubmed #17469677 No free full text.

Abstract: The safety and efficacy of current symptomatic drugs for AD was established using parallel groups taking different doses of active drugs vs placebo over three to twelve months, whereas drugs with potential stabilizing/disease modifying effects are being tested by adding new compounds or placebo to standard symptomatic drugs over 12 to 18 months. Delaying progression to disease milestones may offer additional validity to these studies. It is unclear if biological and neuroimaging markers will add to the clinical evidence.

Touchon J, Portet F, Gauthier S. · Neurology Service, Guy de Chauliac Hospital, Montpellier, France. · Neurology. · Pubmed #17101931 No free full text.

Abstract: Finding strategies that prevent or delay the onset of dementia in Alzheimer disease (AD) will be a challenge for the years to come. Prevention trials in AD pose several unresolved questions, including methodologic, scientific, medical, regulatory, and ethical issues. A critical concern is the benefit and relative risk of giving a treatment to non-demented patients or to asymptomatic subjects. Some trials are under way and will perhaps move the field of prevention of dementia one big step forward.

Vellas B, Gauthier S, Allain H, Andrieu S, Aquino JP, Berrut G, Berthel M, Blanchard F, Camus V, Dartigues JF, Dubois B, Forette F, Franco A, Gonthier R, Grand A, Hervy MP, Jeandel C, Joel ME, Jouanny P, Lebert F, Michot P, Montastruc JL, Nourhashemi F, Ousset PJ, Pariente J, Rigaud AS, Robert P, Ruault G, Strubel D, Touchon J, Verny M, Vetel JM. · No affiliation provided · J Nutr Health Aging. · Pubmed #16222399 No free full text.

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Erkinjuntti T, Román G, Gauthier S. · Helsinki University Central Hospital, Finland. · Neurol Res. · Pubmed #15265282 No free full text.

Abstract: Cerebrovascular disease (CVD), as well as secondary ischemic brain injury from cardiovascular disease, are common causes of dementia and cognitive decline in the elderly. Also, CVD frequently contributes to cognitive loss in patients with Alzheimer's disease (AD). Progress in understanding the pathogenetic mechanism involved in vascular cognitive impairment and vascular dementia (VaD) has resulted in promising treatments of these conditions. Cholinergic deficits in VaD are due to ischemia of basal forebrain nuclei and of cholinergic pathways and can be treated with the use of the cholinesterase inhibitors used in AD. Controlled clinical trials with donepezil, galantamine, and rivastigmine in VaD, as well as in patients with AD plus CVD, have demonstrated improvement in cognition, behavior and activities of daily living.

Gauthier S. · Unité de recherche sur la maladie d'Alzheimer, Centre McGill d'études sur le vieillissement, Québec, Canada H4H 1R3. · Rev Neurol (Paris). · Pubmed #15034487 No free full text.

Abstract: The availability of many etiological hypothesis for Alzheimer's disease raise the possibility of treatments aiming at slowing down disease progression. Clinical trial designs and relevant outcomes are available to test these hypothesis. A preventive approach based on individual risk assessment may be possible, which will increase the number of consultations for neurologists in the near future.

McKeith I, Mintzer J, Aarsland D, Burn D, Chiu H, Cohen-Mansfield J, Dickson D, Dubois B, Duda JE, Feldman H, Gauthier S, Halliday G, Lawlor B, Lippa C, Lopez OL, Carlos Machado J, O'Brien J, Playfer J, Reid W, Anonymous00116. · Institute for Ageing and Health, University of Newcastle, Newcastle upon Tyne, UK. · Lancet Neurol. · Pubmed #14693108 No free full text.

Abstract: Dementia with Lewy bodies (DLB) is the second commonest cause of neurodegenerative dementia in older people. It is part of the range of clinical presentations that share a neuritic pathology based on abnormal aggregation of the synaptic protein alpha-synuclein. DLB has many of the clinical and pathological characteristics of the dementia that occurs during the course of Parkinson's disease. Here we review the current state of scientific knowledge on DLB. Accurate identification of patients is important because they have specific symptoms, impairments, and functional disabilities that differ from those of other common types of dementia. Severe neuroleptic sensitivity reactions are associated with significantly increased morbidity and mortality. Treatment with cholinesterase inhibitors is well tolerated by most patients and substantially improves cognitive and neuropsychiatric symptoms. Clear guidance on the management of DLB is urgently needed. Virtually unrecognised 20 years ago, DLB could within this decade be one of the most treatable neurodegenerative disorders of late life.

Gauthier S, Emre M, Farlow MR, Bullock R, Grossberg GT, Potkin SG. · McGill Centre for Studies in Aging, Verdun, Quebec, Canada. · Curr Med Res Opin. · Pubmed #14687441 No free full text.

Abstract: Cholinesterase (ChE) inhibitors represent the standard therapeutic approach to the treatment of Alzheimer's disease (AD). However, a proportion of patients experience lack or loss of therapeutic benefit with an initial agent, or discontinue due to safety/tolerability issues. In many instances, no alternative treatment is offered once the initial agent has been stopped. Thus, for many patients, the total duration of treatment is relatively short in comparison with the chronic nature of AD. Switching medications is a common therapeutic strategy within many drug classes across many clinical areas following a lack/loss of efficacy or safety/tolerability problems, and is also an increasingly important concept in the management of AD with ChE inhibitors. A number of open-label studies, where patients were switched from donepezil to rivastigmine, have indicated that approximately 50% of patients experiencing a lack/loss of efficacy with donepezil (a selective acetylcholinesterase [AChE] inhibitor) respond to subsequent treatment with rivastigmine (a dual AChE and butyrylcholinesterase inhibitor). In these studies, rivastigmine was well tolerated, and the occurrence of safety/tolerability problems with donepezil was not predictive of similar problems with rivastigmine. In the summer of 2002, leading neurologists and psychiatrists attended a medical experts meeting to discuss the clinical importance of switching ChE inhibitors in AD. The expert panel examined available clinical data, shared clinical experiences, and discussed current clinical guidelines for switching. The panel also aimed to reach consensus on 'whom to switch', 'when to switch' and 'how to switch'. The key findings from that meeting are reported in this review.

Allain H, Bentué-Ferrer D, Tribut O, Gauthier S, Michel BF, Drieu-La Rochelle C. · Laboratoire de Pharmacologie Expérimentale et Clinique, Faculté de Médecine, Université de Rennes I, CS 34317, 35043 Rennes cedex, France. · Fundam Clin Pharmacol. · Pubmed #12914543 No free full text.

Abstract: The current pharmacological treatment of Alzheimer's disease (AD) comes down to four marketed drugs (tacrine, donepezil, rivastigmine and galantamine) all of which are cholinesterase inhibitors, conforming to the cholinergic hypothesis. The future is clearly directed at new biological targets closely linked to the pathophysiology of the disease and more precisely, the pathological hallmark of AD which includes widespread neuronal degeneration, neuritic plaques containing beta-amyloid and tau-rich neurofibrillary tangles. For clinicians, this means that new curative drugs will have to be prescribed early in the course of the disease. This review describes the main entry pathways for drug discovery in AD: (1) supplementation therapy, (2) anti-apoptotic compounds, (3) substances with a mitochondrial impact, (4) anti-amyloid substances, (5) anti-protein aggregation and (6) lipid-lowering drugs. The rapidity at which these compounds will be at our disposal is highly dependent on the policy of the pharmaceutical companies.

Gauthier S. · Alzheimer's Disease Research Unit at the McGill Centre for Studies in Aging, McGill University, Montreal, Que. · CMAJ. · Pubmed #11898943 links to  free full text

This publication has no abstract.

Gauthier S. · Alzheimer's Disease Research Unit, McGill Centre for Studies in Aging, Montreal, Québec, Canada. · Drugs Aging. · Pubmed #11772125 No free full text.

Abstract: Cholinergic adverse effects of acetylcholinesterase inhibitors (AChEIs) are caused by their central and peripheral pharmacological actions on a variety of organ tissues. Gastrointestinal adverse effects predominate and these were relatively common in the phase II and III randomised clinical trials of AChEIs for the treatment of probable Alzheimer's disease. However, in these studies forced and rapid titration of drugs was used, which is not the case in clinical practice. Although there is a risk of pharmacodynamic interactions with other drugs leading to enhanced cholinergic adverse effects, very few of these interactions have proven to be clinically significant. Unresolved issues include the mechanism of syncope and neuromuscular weakness, which should be resolved through structured pharmacovigilance programmes and clinical studies. Loss of bodyweight may prove to be a long term significant complication. As a class, the AChEIs have proven to be well tolerated in the symptomatic treatment of Alzheimer's disease in its mild-to-moderately severe stages. The incidence and clinical significance of cholinergic adverse events will need to be carefully studied if the drugs are used for indications other than Alzheimer's disease.