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C.05.03 Emerging new strategies for early AD diagnosis
C.06. Managing patients with bipolar mania: are our needs being met? and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest 112: 440–449. [2] Kukar T, Golde TE, 2008, Possible mechanisms of action of NSAIDs and related compounds that modulate gamma-secretase cleavage. Curr Top Med Chem 8: 47−53.
C.05.02 Clinical research update – focus on Flurizan R. Green1 ° . USA
1 Boston
University, School of Medicine, Boston,
A number of agents currently in clinical development are designed to intervene at different points along the amyloid cascade – a pathway that is thought to underlie the pathophysiology of Alzheimer’s disease (AD). The impact of these agents may go beyond the symptomatic benefits seen with currently available therapies and alter the course of the disease. If such ’diseasemodifying’ agents are approved and accepted, there will be a major change in the AD treatment paradigm. This presentation will provide a brief review of the amyloid-based interventions currently in late-stage clinical development, while focusing attention on tarenflurbil (Flurizan® ). Tarenflurbil is a selective Ab42-lowering agent (SALA) that modulates gamma-secretase to shift production away from the toxic Ab42 peptide toward the generation of shorter, less-toxic fragments of Ab. Support for the potential benefit of tarenflurbil at a dose of 800 mg bid in subjects with mild AD (MMSE 20−26) was observed in a randomised, double-blind, Phase II trial. Benefit was observed at both 12 and 24 months in activities of daily living and in global function. Tarenflurbil was considered to be well tolerated for up to 24 months of treatment. The Phase III study, designed to assess the efficacy and safety of tarenflurbil in subjects with mild AD (MMSE 20−26), included 1,684 participants randomised at 133 sites throughout the USA. At baseline, the mean age of participants was 74.6 years; 51.1% were female. The mean MMSE score was 23.3 (SD: 2.0; range 20−26). The last patient visit occurred in March 2008. References [1] Wilcock GK, Black SE, Hendrix S, Zavitz K, Laughlin M, Swabb E, 2007, Efficacy and safety of tarenflurbil (flurizan), a selective Ab42lowering agent, in Alzheimer’s disease (AD): a phase 2 trial of up to 24 months of treatment [abstract]. Eur J Neurol 14(Suppl 1): 26. Abstract SC306.
C.05.03 Emerging new strategies for early AD diagnosis B. Dubois1 ° . 1 Hˆopital La Salp´etri`ere, Centre des Maladies Cognitives et Comportementales, Paris Cedex 13, France Today, the diagnosis of Alzheimer’s disease (AD) relies mainly on a two-step process with: 1) the characterisation of a dementia syndrome; and 2) the exclusion of other causes of dementia, based on biological and neuro-imaging exams. Since the publication of the NINCDS-ADRDA criteria in 1984, there is an unprecedented growth of scientific knowledge about AD. Accordingly, it is time to reconsider the diagnosis procedure. Indeed, there is no reason to link the diagnosis of a disease to a threshold of severity (the dementia threshold): AD starts with the first symptoms and we must identify AD in this predementia stage. This is possible if we take into account advances in neuropsychology (specific memory disorders), biology (specific
S593
CSF biomarkers) and neuro-imaging (atrophy of mediotemporal lobe structure or specific pattern on molecular neuro-imaging). With the new criteria, it is now possible to capture both the earliest stages, before full-blown dementia, as well as the full spectrum of the illness. The timeliness of these criteria is underscored by the number of drugs currently under development that are directed at altering the disease pathogenesis, particularly at the production and clearance of beta amyloid as well as the hyperphosphorylation state of tau. The usefulness will be determined in the future as investigators apply the criteria in a variety of research studies, and as key issues in their application are resolved.
C.06. Managing patients with bipolar mania: are our needs being met? C.06.01 Treating manic symptoms: from theory to practice G. Sachs1 ° . 1 Massachusetts General Hospital, Bipolar Clinic and Research Program, Boston, USA Early recognition and treatment of manic episodes is essential for effective management of bipolar disorder, and is important for the longer-term outcome for patients. A key aim in the management of bipolar disorder is the long-term maintenance of patients in symptom-free remission. Pharmacological treatment of acute mania in bipolar disorder is commonly centred around the classic antimanic agent, lithium, and anticonvulsants such as carbamazepine and sodium valproate. However, up to 50% of patients fail to respond to these therapies, efficacy being particularly low in mixed episodes, and where rapid cycling or psychotic symptoms are present. Also, the poor toxicity profiles and debilitating sideeffects of some of these medications add to the risk of noncompliance, which increases the likelihood of relapse. This is also true where patients are treated with typical antipsychotics, since patients with bipolar disorder are particularly vulnerable to the debilitating effects of akathisia and other extrapyramidal symptoms. The use of atypical antipsychotics with more acceptable tolerability profiles has provided an effective alternative in the treatment of acute mania, in some cases reducing the likelihood of rebound into depression and the severity of depression in mixed episodes. However, individual atypical agents may be associated with other side effects, such as weight gain, hyperprolactinaemia, and QTc prolongation, which may limit the value and tolerability of treatment. Treatment adherence, correlated with tolerability, has a strong influence on the maintenance of effect observed with therapy. Such factors are critical to real-world treatment success in bipolar mania. C.06.02 Building an effective therapeutic alliance with our patients J. Goikolea1 ° . 1 Bipolar Disorders Program Clinical Institute of Neuroscience Hospital Clinic Institut d’Investigacions Biom´ediques August Pi Sunyer, Barcelona Stanley Foundation Center, Barcelona, Spain Bipolar disorder is characterized by depressive, manic and mixed (including both depressive and manic symptoms) episodes, which typically recur throughout the individual’s lifetime, often with increasing frequency, duration and intensity. The impact of an acute
C.05.02 Clinical research update – focus on Flurizan R. Green1 ° . USA
1 Boston
University, School of Medicine, Boston,
A number of agents currently in clinical development are designed to intervene at different points along the amyloid cascade – a pathway that is thought to underlie the pathophysiology of Alzheimer’s disease (AD). The impact of these agents may go beyond the symptomatic benefits seen with currently available therapies and alter the course of the disease. If such ’diseasemodifying’ agents are approved and accepted, there will be a major change in the AD treatment paradigm. This presentation will provide a brief review of the amyloid-based interventions currently in late-stage clinical development, while focusing attention on tarenflurbil (Flurizan® ). Tarenflurbil is a selective Ab42-lowering agent (SALA) that modulates gamma-secretase to shift production away from the toxic Ab42 peptide toward the generation of shorter, less-toxic fragments of Ab. Support for the potential benefit of tarenflurbil at a dose of 800 mg bid in subjects with mild AD (MMSE 20−26) was observed in a randomised, double-blind, Phase II trial. Benefit was observed at both 12 and 24 months in activities of daily living and in global function. Tarenflurbil was considered to be well tolerated for up to 24 months of treatment. The Phase III study, designed to assess the efficacy and safety of tarenflurbil in subjects with mild AD (MMSE 20−26), included 1,684 participants randomised at 133 sites throughout the USA. At baseline, the mean age of participants was 74.6 years; 51.1% were female. The mean MMSE score was 23.3 (SD: 2.0; range 20−26). The last patient visit occurred in March 2008. References [1] Wilcock GK, Black SE, Hendrix S, Zavitz K, Laughlin M, Swabb E, 2007, Efficacy and safety of tarenflurbil (flurizan), a selective Ab42lowering agent, in Alzheimer’s disease (AD): a phase 2 trial of up to 24 months of treatment [abstract]. Eur J Neurol 14(Suppl 1): 26. Abstract SC306.
C.05.03 Emerging new strategies for early AD diagnosis B. Dubois1 ° . 1 Hˆopital La Salp´etri`ere, Centre des Maladies Cognitives et Comportementales, Paris Cedex 13, France Today, the diagnosis of Alzheimer’s disease (AD) relies mainly on a two-step process with: 1) the characterisation of a dementia syndrome; and 2) the exclusion of other causes of dementia, based on biological and neuro-imaging exams. Since the publication of the NINCDS-ADRDA criteria in 1984, there is an unprecedented growth of scientific knowledge about AD. Accordingly, it is time to reconsider the diagnosis procedure. Indeed, there is no reason to link the diagnosis of a disease to a threshold of severity (the dementia threshold): AD starts with the first symptoms and we must identify AD in this predementia stage. This is possible if we take into account advances in neuropsychology (specific memory disorders), biology (specific
S593
CSF biomarkers) and neuro-imaging (atrophy of mediotemporal lobe structure or specific pattern on molecular neuro-imaging). With the new criteria, it is now possible to capture both the earliest stages, before full-blown dementia, as well as the full spectrum of the illness. The timeliness of these criteria is underscored by the number of drugs currently under development that are directed at altering the disease pathogenesis, particularly at the production and clearance of beta amyloid as well as the hyperphosphorylation state of tau. The usefulness will be determined in the future as investigators apply the criteria in a variety of research studies, and as key issues in their application are resolved.
C.06. Managing patients with bipolar mania: are our needs being met? C.06.01 Treating manic symptoms: from theory to practice G. Sachs1 ° . 1 Massachusetts General Hospital, Bipolar Clinic and Research Program, Boston, USA Early recognition and treatment of manic episodes is essential for effective management of bipolar disorder, and is important for the longer-term outcome for patients. A key aim in the management of bipolar disorder is the long-term maintenance of patients in symptom-free remission. Pharmacological treatment of acute mania in bipolar disorder is commonly centred around the classic antimanic agent, lithium, and anticonvulsants such as carbamazepine and sodium valproate. However, up to 50% of patients fail to respond to these therapies, efficacy being particularly low in mixed episodes, and where rapid cycling or psychotic symptoms are present. Also, the poor toxicity profiles and debilitating sideeffects of some of these medications add to the risk of noncompliance, which increases the likelihood of relapse. This is also true where patients are treated with typical antipsychotics, since patients with bipolar disorder are particularly vulnerable to the debilitating effects of akathisia and other extrapyramidal symptoms. The use of atypical antipsychotics with more acceptable tolerability profiles has provided an effective alternative in the treatment of acute mania, in some cases reducing the likelihood of rebound into depression and the severity of depression in mixed episodes. However, individual atypical agents may be associated with other side effects, such as weight gain, hyperprolactinaemia, and QTc prolongation, which may limit the value and tolerability of treatment. Treatment adherence, correlated with tolerability, has a strong influence on the maintenance of effect observed with therapy. Such factors are critical to real-world treatment success in bipolar mania. C.06.02 Building an effective therapeutic alliance with our patients J. Goikolea1 ° . 1 Bipolar Disorders Program Clinical Institute of Neuroscience Hospital Clinic Institut d’Investigacions Biom´ediques August Pi Sunyer, Barcelona Stanley Foundation Center, Barcelona, Spain Bipolar disorder is characterized by depressive, manic and mixed (including both depressive and manic symptoms) episodes, which typically recur throughout the individual’s lifetime, often with increasing frequency, duration and intensity. The impact of an acute