- Email: [email protected]
Effect of Physical Exercise on Alzheimer's Disease
S24
Abstracts / Neurobiology of Aging 35 (2014) S1eS27
After modest success in bringing symptomatic therapy to the clinic, there is still high drug discovery need for effective disease-modifying treatment for the worldwide exploding epidemic of Alzheimer’s disease (AD). Such trial are more likely to be successful if we start earl the onset of dementia. From the development of the first transgenic mouse model of brain amyloidosis, and the report on the effect of active immunization against aggregated amyloid peptide on this model, anti-amyloid immunotherapy has been the leading strategy for disease-modifying drug development. However progress has been slow. While efforts turned to the development of safer active vaccines, using short sequence antigens to minimize toxicity mediated by cellular immunity, many investigators sought development of passive immunotherapy. Several monoclonal anti-amyloid antibodies have advanced into mid- and late-phase trials. Phase III trial program involving four thousand individuals with mild to moderate AD, bapineuzumab did not demonstrate a favorable impact on the primary cognitive and functional measures. Two phase III studies of solanezumab failed on their primary cognitive and functional measures; however, planned, post-hoc pooled analyses of individuals with mild AD dementia did show cognitive benefit with treatment. It was concluded that trials have to be started earlier before the dementia stage. So the development of solanezumap agent for the treatment of AD dementia will continue with a clinical trial already started in mild dementia and a large trial in asymptomatic subjects but with brain amyloid signature the A4 trial. In contrast to bapineuzumab, solanezumab is a humanized monoclonal antibody that targets a mid-sequence amyloid peptide epitope. This antibody binds tightly to monomeric amyloid peptides, but not to aggregated or fibrillar forms. Crenezumab an other monoclonal antibody binds to a mid-sequence epitope, but differs from solenazumab in that it possesses an IgG4 (rather than IgG1), so that it triggers less cytokine production from microglia while maintaining phagocytosis towards amyloid. Gantenerumab is a fully human monoclonal antibody that binds to both N-terminus and mid-sequence epitopes, and shows high affinity for fibrils. Like bapineuzumab, early studies demonstrated that treatment reduced brain amyloid as indicated by PET imaging, supporting target engagement. Trials in mild to moderate AD and prodromal AD are under way. SAR228810 is a humanized antibody that recognizes a particular conformational epitope that allows it to bind specifically protofibrils and fibrils. A phase II single clinical study in patients with ProDromal Alzheimers Disease is ongoing. Other trials in pro-dromal AD or so called amyloid MCI are also started with the merck BACE inhibitor. Secondary prevention trials, at very early stage of the disease, seem much more likely than the recent dementia-stage trials to demonstrate beneficial effects of antiamyloid therapy on clinical progression. Several bace inhibitor are also in progress as well that new drugs targeting tau. Other approaches include multidomain preventive trials, eg nutrition intervention plus physical and cognitive exercise several projects have been funded worldwide. In this lecture an update will be presented on current drug trials in Alzheimer’s disease focusing on preventive trials in Alzheimer’s Disease
NEW DEVELOPMENTS IN MOLECULAR IMAGING OF THE PATHOLOGY OF NEURODEGENERATION Victor L. Villemagne1,2,3. 1 Department of Nuclear Medicine and Centre for PET, Austin Health, Melbourne, Australia; 2 The Florey Institute for Neurosciences and Mental Health, The University of Melbourne, Australia; 3 Department of Medicine, The University of Melbourne, Australia. E-mail: [email protected]
prognostic certainty required, especially for the identification of at-risk individuals before the development of the typical phenotype. Consequently, a multimodality approach for the accurate and early diagnosis, monitoring disease progression, and better treatment follow-up of AD is warranted. Molecular imaging techniques such as positron emission tomography (PET) can be used for the characterization and quantification of disease specific traits such as Ab or tau. In vivo Ab imaging has transformed the assessment of AD pathology and its changes over time, extending our insight into Ab deposition in the brain by providing highly accurate, reliable, and reproducible quantitative statements of regional or global Ab burden in the brain, essential for therapeutic trial recruitment and for the evaluation of anti- Ab treatments. There are several radiotracers for the in vivo evaluation of Ab burden in the brain, some of them already approved for clinical use. In recent years there has been significant progress in the development of tau imaging tracers. In vivo selective tau imaging will allow new insights into tau pathology in the human brain, facilitating research into causes, diagnosis and treatment of traumatic encephalopathy and major neurodegenerative dementias, such as AD and some variants of frontotemporal lobar degeneration, where tau plays a role. The field of selective tau imaging overcame several obstacles, some of them associated with the idiosyncrasies of tau aggregation and others related to radiotracer design. Recent progress in the development of these tracers is enabling the non-invasive assessment of the extent of tau pathology in the brain, eventually allowing the quantification of changes in tau pathology over time and its relation to cognitive performance, brain volumetrics and other biomarkers, as well as assessment of efficacy and patient recruitment for anti-tau therapeutic trials.
RECENT ADVANCES IN TAU IMAGING Victor L. Villemagne. Austin Health, Melbourne, VIC, Australia. E-mail: [email protected] In vivo selective tau imaging will allow new insights into tau pathology in the human brain, facilitating research into causes, diagnosis and treatment of traumatic encephalopathy and major neurodegenerative dementias, such as Alzheimer’s disease and some variants of frontotemporal lobar degeneration, where tau plays a role. The field of selective tau imaging has to overcome several obstacles, some of them associated with the idiosyncrasies of tau aggregation and others related to radiotracer design. A worldwide effort has focused on the development of imaging agents that will allow selective tau imaging in vivo. Recent progress in the development of these tracers is enabling the non-invasive assessment of the extent of tau pathology in the brain, eventually allowing the quantification of changes in tau pathology over time and its relation to cognitive performance, brain volumetrics and other biomarkers, as well as assessment of efficacy and patient recruitment for anti-tau therapeutic trials. Keywords. Tau imaging, Alzheimer’s disease, Tauopathies
EFFECT OF PHYSICAL EXERCISE ON ALZHEIMER’S DISEASE
b-amyloid (Ab) and tau are the neuropathological hallmarks of Alzheimer’s
Gunhild Waldemar, S.G. Hasselbalch. Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. E-mail: [email protected]
disease (AD). As new treatment strategies to prevent or slow disease progression through early-intervention are being developed and implemented, there is an urgent need for early disease recognition, which is reflected in the necessity of developing sensitive and specific biomarkers as adjuncts to clinical and neuropsychological tests. Because the molecular changes occur well before the phenotypical manifestation of the disease, a change in the diagnostic paradigm is needed, where diagnosis moves away from the identification of signs and symptoms of neuronal failure to the early and non-invasive detection of a particular trait or traits underlying the pathological process, that will also allow evaluation of efficacy and monitoring the effects of disease-modifying therapies. Based on the role these aggregated proteins play along the disease spectrum and how they are applied, molecular imaging techniques can be used as antecedent, diagnostic, prognostic and/or theragnostic biomarkers. Given the complexity and sometimes overlapping characteristics of these neurodegenerative conditions, it is unlikely that a single biomarker will be able to provide the diagnostic or
In recent years, there has been an increasing interest in the potential health benefits of physical activity in both healthy elderly subject and in patients with Alzheimer’s disease (AD). This interest stems primarily from large wellconducted population studies showing a substantial decrease in the risk of AD in physically active subjects with a risk reduction ratio of 0.4 to 0.8. Conversely, low levels of exercise is one of the greatest risk factors for agerelated decline. Several experimental studies on AD using transgenic mice models have documented a marked effect from physical exercise on memory. Exercise seems to affect several levels of the “b-amyloid cascade” by increasing neurogenesis from stem cells in the hippocampus due to an increase in nerve growth factors, by inhibiting apoptotic biochemical cascades and by restoring normal levels of glucose and insulin, as well as by downregulating pro-inflammatory genes combined with an up-regulation of antiinflammatory factors. Perhaps most importantly, mouse models show that physical exercise significantly reduces b-amyloid accumulation, thereby
Abstracts / Neurobiology of Aging 35 (2014) S1eS27
diminishing the detrimental effects of the cascade reaction. Thus, based on experimental studies, there is a theoretical rationale for an effect from physical exercise on cognitive performance and function in AD. In humans both short term and long term exercise is associated with improved learning and memory and with the induction of Brain Derived Neurotrophic Factor (BDNF), an important plasticity-related neurotrophin. Although some clinical trials on various forms of physical activity have been performed on moderate to severe AD subjects, there is insufficient evidence for an effect of physical exercise in subjects with dementia, primarily due to lack of appropriately designed studies. Thus, to which extent moderate to high intensity physical exercise may prevent dementia or slow down the disease process in AD is not yet clear. Several large randomized controlled trials on the effect of physical exercise on prevention of dementia and functional outcome in healthy elderly subjects or subjects with subjective cognitive symptoms, recruited from population studies, are now ongoing. However, only few studies have as yet evaluated the effect of aerobic exercise on cognition in MCI or mild AD.
S25
atrophy. Some SVD markers may have a particularly valuable role in identifying the underlying small vessel arteriopathy; for example, a strictly lobar pattern of CMBs is suggestive of CAA, while deep CMBs more likely reflect hypertensive arteriopathy. Of the small vessel diseases, cerebral amyloid angiopathy (CAA) is of particular interest in dementia research because of the overlap and potential interaction with AD. Detecting CAA has potential importance in the following ways: for the prediction and monitoring of AD treatment-related complications (especially from immunotherapy); understanding disease mechanisms and clinical features; and in assessing bleeding risk. In this presentation recent progress in developing diagnostic and prognostic neuroimaging biomarkers for CAA will be reviewed, highlighting the relevance to dementia research wherever possible. In addition to CMBs, we will consider the topography of MRIvisible perivascular spaces and cortical superficial siderosis as characteristic neuroimaging markers of CAA with relevance for diagnosis, understanding and monitoring CAA. Keywords. MRI, Small vessel disease, Cerebral amyloid Angiopathy
Keywords. Alzheimer’s disease, Dementia, Physical exercise
FACTORS THAT AFFECT LIFESPAN IN MILD VERSUS MODERATE ALZHEIMER’S DISEASE
SHIFTED FOCUS FOR TARGET ORIENTED BASIC RESEARCH IN ALZHEIMER DISEASE
Carina Wattmo, E. Londos, L. Minthon. Clinical Memory Research Unit, Dept. of Clinical Sciences, Malmö, Lund University, Malmö, Sweden. E-mail: [email protected]
Bengt Winblad. Karolinska Institutet Alzheimer Disease Research Cente, Stockholm, Sweden. E-mail: [email protected]
Background/objectives. Increased knowledge of the factors that might affect lifespan in Alzheimer’s disease (AD) patients treated with cholinesterase inhibitors (ChEIs) is important for clinicians and for the health services. Moreover, future disease-modifying therapies might affect survival. We aimed to identify factors that influence life expectancy in the mild vs. moderate stage of ChEI-treated AD. Methods. The Swedish Alzheimer Treatment Study (SATS) is a prospective, observational, multicentre study for the assessment of ChEI treatment in a routine clinical setting. This presentation included 791 deceased participants with a clinical diagnosis of AD. Of those, 538 were defined as mild (MiniMental State Examination (MMSE) score, 20e26) and 253 as moderate (MMSE score, 10e19) AD at the start of ChEI therapy (shortly after the time of diagnosis). The patients’ date of death was recorded and their survival was individually compared with the sex- and age-matched general population. Results. The mean standard deviation time from AD diagnosis to death was 5.93 2.88 years in the mild and 5.32 2.44 years in the moderate stage (p ¼ 0.002). This difference was not observed in the youngest and oldest age groups, in those with more years of education, or in the sex- or apolipoprotein E (APOE)specific subgroups. Compared with the general population, a decrease in expected lifespan was found in the mild and moderate AD patients (40% vs. 47%, p ¼ 0.002). Highly educated individuals or carriers of two APOE e4 alleles in the moderate stage exhibited great reductions in life expectancy (57%). Conclusion. The survival time after diagnosis in the mild vs. moderate stage might be similar in subgroups of AD, suggesting that genetic and socio-demographic factors have a strong impact on lifespan, even among AD patients. Higher education or carrying two APOE e4 alleles were risk factors for increased mortality in the more advanced stage.
Research into AD has been partly successful in terms of developing symptomatic treatments, but has also had several failures in terms of developing disease-modifying therapies. The last drug to enter the market was in 2002. Since then, many products in different development phases have failed. Why? Wrong target, wrong molecules, inappropriate animal models, inappropriate proof-of-concept studies, heterogeneous patient groups, too advanced disease, non-relevant outcome measures, inter-centre variability in increasingly globalised multi-centre trials? Many clinical and experimental studies are ongoing, mainly based on anti-amyloid-b (Ab) strategies, but the exact role played by Ab in AD pathogenesis is not yet clear. We need to acknowledge that a single cure for AD is unlikely to be found and that the approach to drug development for this disorder needs to be reconsidered. Preclinical research is constantly providing us with new information of the complex AD puzzle, and an analysis of this information might reveal patterns of pharmacological interactions instead of single potential drug targets. Increased collaboration between pharmaceutical companies, basic and clinical researchers will bring us closer to developing an optimal pharmaceutical approach for the treatment of AD. A better understanding of the disease pathogenesis will hopefully be the way forward to finding relevant targets in order to optimize treatment for AD. Keywords. Alzheimer disease, Drug targets, Treatment strategies
WHY DID ANIMAL MODELS FAIL TO SHOW THE RIGHT WAY TO ALZHEIMER THERAPY?
Keywords. Alzheimer’s disease, Risk factors, Mortality Manfred Windisch. NeuroScios GmbH, St. Radegund/Graz, Austria. E-mail: [email protected]
MRI MARKERS OF HEMORRHAGIC RISK
MICROVASCULAR
PATHOLOGY
AND
David J. Werring. UCL Institute of Neurology, National Hospital, Queen Square City, London, GB. E-mail: [email protected] Neurodegenerative diseases, including sporadic Alzheimer’s disease (AD), almost invariably coexist with cerebrovascular disease in older people. Cerebral small vessel disease (SVD) is the most important vascular contribution to dementia, causes about a fifth of all ischaemic strokes, and most cases of spontaneous intracerebral haemorrhage. Developments in neuroimaging, especially magnetic resonance imaging (MRI) now detect an increasing number of potential biomarkers of SVD. These include small subcortical infarcts, white matter magnetic resonance (MR) hyperintensities, lacunes, prominent perivascular spaces, cerebral microbleeds (CMBs), cortical superficial siderosis, and
The fact that there are no naturally occurring animal models of Alzheimer’s disease (AD) available, makes it necessary to create artificial systems, either by induction of lesions or by genectic manipulation. Majority of AD models different transgenic rodents, over-expressing disease relevant proteins like APP or tau that are believed to be involved in the pathogenesis. In spite of enormous efforts no real complete model could be established so far, that really replicates the proposed disease cascade. High levels of over production of different mutated proteins that do never exist in a single patient question already any translational value. On the other hand it is a fact that treatment effects on different disease targets like beta-secretase could be reproduced in human clinical trial, but biochemical changes did not result in functional improvements. It seems obvious that cognitive changes that were shown in rats and mice as a consequence of the genetic manipulation or the lesion are most likely not the cause of cognitive disturbance in humans. This lack of correlation leads to wrong conclusions in selection of new treatments for clinical testing. So the selection of models was already critical, but in addition
Abstracts / Neurobiology of Aging 35 (2014) S1eS27
After modest success in bringing symptomatic therapy to the clinic, there is still high drug discovery need for effective disease-modifying treatment for the worldwide exploding epidemic of Alzheimer’s disease (AD). Such trial are more likely to be successful if we start earl the onset of dementia. From the development of the first transgenic mouse model of brain amyloidosis, and the report on the effect of active immunization against aggregated amyloid peptide on this model, anti-amyloid immunotherapy has been the leading strategy for disease-modifying drug development. However progress has been slow. While efforts turned to the development of safer active vaccines, using short sequence antigens to minimize toxicity mediated by cellular immunity, many investigators sought development of passive immunotherapy. Several monoclonal anti-amyloid antibodies have advanced into mid- and late-phase trials. Phase III trial program involving four thousand individuals with mild to moderate AD, bapineuzumab did not demonstrate a favorable impact on the primary cognitive and functional measures. Two phase III studies of solanezumab failed on their primary cognitive and functional measures; however, planned, post-hoc pooled analyses of individuals with mild AD dementia did show cognitive benefit with treatment. It was concluded that trials have to be started earlier before the dementia stage. So the development of solanezumap agent for the treatment of AD dementia will continue with a clinical trial already started in mild dementia and a large trial in asymptomatic subjects but with brain amyloid signature the A4 trial. In contrast to bapineuzumab, solanezumab is a humanized monoclonal antibody that targets a mid-sequence amyloid peptide epitope. This antibody binds tightly to monomeric amyloid peptides, but not to aggregated or fibrillar forms. Crenezumab an other monoclonal antibody binds to a mid-sequence epitope, but differs from solenazumab in that it possesses an IgG4 (rather than IgG1), so that it triggers less cytokine production from microglia while maintaining phagocytosis towards amyloid. Gantenerumab is a fully human monoclonal antibody that binds to both N-terminus and mid-sequence epitopes, and shows high affinity for fibrils. Like bapineuzumab, early studies demonstrated that treatment reduced brain amyloid as indicated by PET imaging, supporting target engagement. Trials in mild to moderate AD and prodromal AD are under way. SAR228810 is a humanized antibody that recognizes a particular conformational epitope that allows it to bind specifically protofibrils and fibrils. A phase II single clinical study in patients with ProDromal Alzheimers Disease is ongoing. Other trials in pro-dromal AD or so called amyloid MCI are also started with the merck BACE inhibitor. Secondary prevention trials, at very early stage of the disease, seem much more likely than the recent dementia-stage trials to demonstrate beneficial effects of antiamyloid therapy on clinical progression. Several bace inhibitor are also in progress as well that new drugs targeting tau. Other approaches include multidomain preventive trials, eg nutrition intervention plus physical and cognitive exercise several projects have been funded worldwide. In this lecture an update will be presented on current drug trials in Alzheimer’s disease focusing on preventive trials in Alzheimer’s Disease
NEW DEVELOPMENTS IN MOLECULAR IMAGING OF THE PATHOLOGY OF NEURODEGENERATION Victor L. Villemagne1,2,3. 1 Department of Nuclear Medicine and Centre for PET, Austin Health, Melbourne, Australia; 2 The Florey Institute for Neurosciences and Mental Health, The University of Melbourne, Australia; 3 Department of Medicine, The University of Melbourne, Australia. E-mail: [email protected]
prognostic certainty required, especially for the identification of at-risk individuals before the development of the typical phenotype. Consequently, a multimodality approach for the accurate and early diagnosis, monitoring disease progression, and better treatment follow-up of AD is warranted. Molecular imaging techniques such as positron emission tomography (PET) can be used for the characterization and quantification of disease specific traits such as Ab or tau. In vivo Ab imaging has transformed the assessment of AD pathology and its changes over time, extending our insight into Ab deposition in the brain by providing highly accurate, reliable, and reproducible quantitative statements of regional or global Ab burden in the brain, essential for therapeutic trial recruitment and for the evaluation of anti- Ab treatments. There are several radiotracers for the in vivo evaluation of Ab burden in the brain, some of them already approved for clinical use. In recent years there has been significant progress in the development of tau imaging tracers. In vivo selective tau imaging will allow new insights into tau pathology in the human brain, facilitating research into causes, diagnosis and treatment of traumatic encephalopathy and major neurodegenerative dementias, such as AD and some variants of frontotemporal lobar degeneration, where tau plays a role. The field of selective tau imaging overcame several obstacles, some of them associated with the idiosyncrasies of tau aggregation and others related to radiotracer design. Recent progress in the development of these tracers is enabling the non-invasive assessment of the extent of tau pathology in the brain, eventually allowing the quantification of changes in tau pathology over time and its relation to cognitive performance, brain volumetrics and other biomarkers, as well as assessment of efficacy and patient recruitment for anti-tau therapeutic trials.
RECENT ADVANCES IN TAU IMAGING Victor L. Villemagne. Austin Health, Melbourne, VIC, Australia. E-mail: [email protected] In vivo selective tau imaging will allow new insights into tau pathology in the human brain, facilitating research into causes, diagnosis and treatment of traumatic encephalopathy and major neurodegenerative dementias, such as Alzheimer’s disease and some variants of frontotemporal lobar degeneration, where tau plays a role. The field of selective tau imaging has to overcome several obstacles, some of them associated with the idiosyncrasies of tau aggregation and others related to radiotracer design. A worldwide effort has focused on the development of imaging agents that will allow selective tau imaging in vivo. Recent progress in the development of these tracers is enabling the non-invasive assessment of the extent of tau pathology in the brain, eventually allowing the quantification of changes in tau pathology over time and its relation to cognitive performance, brain volumetrics and other biomarkers, as well as assessment of efficacy and patient recruitment for anti-tau therapeutic trials. Keywords. Tau imaging, Alzheimer’s disease, Tauopathies
EFFECT OF PHYSICAL EXERCISE ON ALZHEIMER’S DISEASE
b-amyloid (Ab) and tau are the neuropathological hallmarks of Alzheimer’s
Gunhild Waldemar, S.G. Hasselbalch. Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. E-mail: [email protected]
disease (AD). As new treatment strategies to prevent or slow disease progression through early-intervention are being developed and implemented, there is an urgent need for early disease recognition, which is reflected in the necessity of developing sensitive and specific biomarkers as adjuncts to clinical and neuropsychological tests. Because the molecular changes occur well before the phenotypical manifestation of the disease, a change in the diagnostic paradigm is needed, where diagnosis moves away from the identification of signs and symptoms of neuronal failure to the early and non-invasive detection of a particular trait or traits underlying the pathological process, that will also allow evaluation of efficacy and monitoring the effects of disease-modifying therapies. Based on the role these aggregated proteins play along the disease spectrum and how they are applied, molecular imaging techniques can be used as antecedent, diagnostic, prognostic and/or theragnostic biomarkers. Given the complexity and sometimes overlapping characteristics of these neurodegenerative conditions, it is unlikely that a single biomarker will be able to provide the diagnostic or
In recent years, there has been an increasing interest in the potential health benefits of physical activity in both healthy elderly subject and in patients with Alzheimer’s disease (AD). This interest stems primarily from large wellconducted population studies showing a substantial decrease in the risk of AD in physically active subjects with a risk reduction ratio of 0.4 to 0.8. Conversely, low levels of exercise is one of the greatest risk factors for agerelated decline. Several experimental studies on AD using transgenic mice models have documented a marked effect from physical exercise on memory. Exercise seems to affect several levels of the “b-amyloid cascade” by increasing neurogenesis from stem cells in the hippocampus due to an increase in nerve growth factors, by inhibiting apoptotic biochemical cascades and by restoring normal levels of glucose and insulin, as well as by downregulating pro-inflammatory genes combined with an up-regulation of antiinflammatory factors. Perhaps most importantly, mouse models show that physical exercise significantly reduces b-amyloid accumulation, thereby
Abstracts / Neurobiology of Aging 35 (2014) S1eS27
diminishing the detrimental effects of the cascade reaction. Thus, based on experimental studies, there is a theoretical rationale for an effect from physical exercise on cognitive performance and function in AD. In humans both short term and long term exercise is associated with improved learning and memory and with the induction of Brain Derived Neurotrophic Factor (BDNF), an important plasticity-related neurotrophin. Although some clinical trials on various forms of physical activity have been performed on moderate to severe AD subjects, there is insufficient evidence for an effect of physical exercise in subjects with dementia, primarily due to lack of appropriately designed studies. Thus, to which extent moderate to high intensity physical exercise may prevent dementia or slow down the disease process in AD is not yet clear. Several large randomized controlled trials on the effect of physical exercise on prevention of dementia and functional outcome in healthy elderly subjects or subjects with subjective cognitive symptoms, recruited from population studies, are now ongoing. However, only few studies have as yet evaluated the effect of aerobic exercise on cognition in MCI or mild AD.
S25
atrophy. Some SVD markers may have a particularly valuable role in identifying the underlying small vessel arteriopathy; for example, a strictly lobar pattern of CMBs is suggestive of CAA, while deep CMBs more likely reflect hypertensive arteriopathy. Of the small vessel diseases, cerebral amyloid angiopathy (CAA) is of particular interest in dementia research because of the overlap and potential interaction with AD. Detecting CAA has potential importance in the following ways: for the prediction and monitoring of AD treatment-related complications (especially from immunotherapy); understanding disease mechanisms and clinical features; and in assessing bleeding risk. In this presentation recent progress in developing diagnostic and prognostic neuroimaging biomarkers for CAA will be reviewed, highlighting the relevance to dementia research wherever possible. In addition to CMBs, we will consider the topography of MRIvisible perivascular spaces and cortical superficial siderosis as characteristic neuroimaging markers of CAA with relevance for diagnosis, understanding and monitoring CAA. Keywords. MRI, Small vessel disease, Cerebral amyloid Angiopathy
Keywords. Alzheimer’s disease, Dementia, Physical exercise
FACTORS THAT AFFECT LIFESPAN IN MILD VERSUS MODERATE ALZHEIMER’S DISEASE
SHIFTED FOCUS FOR TARGET ORIENTED BASIC RESEARCH IN ALZHEIMER DISEASE
Carina Wattmo, E. Londos, L. Minthon. Clinical Memory Research Unit, Dept. of Clinical Sciences, Malmö, Lund University, Malmö, Sweden. E-mail: [email protected]
Bengt Winblad. Karolinska Institutet Alzheimer Disease Research Cente, Stockholm, Sweden. E-mail: [email protected]
Background/objectives. Increased knowledge of the factors that might affect lifespan in Alzheimer’s disease (AD) patients treated with cholinesterase inhibitors (ChEIs) is important for clinicians and for the health services. Moreover, future disease-modifying therapies might affect survival. We aimed to identify factors that influence life expectancy in the mild vs. moderate stage of ChEI-treated AD. Methods. The Swedish Alzheimer Treatment Study (SATS) is a prospective, observational, multicentre study for the assessment of ChEI treatment in a routine clinical setting. This presentation included 791 deceased participants with a clinical diagnosis of AD. Of those, 538 were defined as mild (MiniMental State Examination (MMSE) score, 20e26) and 253 as moderate (MMSE score, 10e19) AD at the start of ChEI therapy (shortly after the time of diagnosis). The patients’ date of death was recorded and their survival was individually compared with the sex- and age-matched general population. Results. The mean standard deviation time from AD diagnosis to death was 5.93 2.88 years in the mild and 5.32 2.44 years in the moderate stage (p ¼ 0.002). This difference was not observed in the youngest and oldest age groups, in those with more years of education, or in the sex- or apolipoprotein E (APOE)specific subgroups. Compared with the general population, a decrease in expected lifespan was found in the mild and moderate AD patients (40% vs. 47%, p ¼ 0.002). Highly educated individuals or carriers of two APOE e4 alleles in the moderate stage exhibited great reductions in life expectancy (57%). Conclusion. The survival time after diagnosis in the mild vs. moderate stage might be similar in subgroups of AD, suggesting that genetic and socio-demographic factors have a strong impact on lifespan, even among AD patients. Higher education or carrying two APOE e4 alleles were risk factors for increased mortality in the more advanced stage.
Research into AD has been partly successful in terms of developing symptomatic treatments, but has also had several failures in terms of developing disease-modifying therapies. The last drug to enter the market was in 2002. Since then, many products in different development phases have failed. Why? Wrong target, wrong molecules, inappropriate animal models, inappropriate proof-of-concept studies, heterogeneous patient groups, too advanced disease, non-relevant outcome measures, inter-centre variability in increasingly globalised multi-centre trials? Many clinical and experimental studies are ongoing, mainly based on anti-amyloid-b (Ab) strategies, but the exact role played by Ab in AD pathogenesis is not yet clear. We need to acknowledge that a single cure for AD is unlikely to be found and that the approach to drug development for this disorder needs to be reconsidered. Preclinical research is constantly providing us with new information of the complex AD puzzle, and an analysis of this information might reveal patterns of pharmacological interactions instead of single potential drug targets. Increased collaboration between pharmaceutical companies, basic and clinical researchers will bring us closer to developing an optimal pharmaceutical approach for the treatment of AD. A better understanding of the disease pathogenesis will hopefully be the way forward to finding relevant targets in order to optimize treatment for AD. Keywords. Alzheimer disease, Drug targets, Treatment strategies
WHY DID ANIMAL MODELS FAIL TO SHOW THE RIGHT WAY TO ALZHEIMER THERAPY?
Keywords. Alzheimer’s disease, Risk factors, Mortality Manfred Windisch. NeuroScios GmbH, St. Radegund/Graz, Austria. E-mail: [email protected]
MRI MARKERS OF HEMORRHAGIC RISK
MICROVASCULAR
PATHOLOGY
AND
David J. Werring. UCL Institute of Neurology, National Hospital, Queen Square City, London, GB. E-mail: [email protected] Neurodegenerative diseases, including sporadic Alzheimer’s disease (AD), almost invariably coexist with cerebrovascular disease in older people. Cerebral small vessel disease (SVD) is the most important vascular contribution to dementia, causes about a fifth of all ischaemic strokes, and most cases of spontaneous intracerebral haemorrhage. Developments in neuroimaging, especially magnetic resonance imaging (MRI) now detect an increasing number of potential biomarkers of SVD. These include small subcortical infarcts, white matter magnetic resonance (MR) hyperintensities, lacunes, prominent perivascular spaces, cerebral microbleeds (CMBs), cortical superficial siderosis, and
The fact that there are no naturally occurring animal models of Alzheimer’s disease (AD) available, makes it necessary to create artificial systems, either by induction of lesions or by genectic manipulation. Majority of AD models different transgenic rodents, over-expressing disease relevant proteins like APP or tau that are believed to be involved in the pathogenesis. In spite of enormous efforts no real complete model could be established so far, that really replicates the proposed disease cascade. High levels of over production of different mutated proteins that do never exist in a single patient question already any translational value. On the other hand it is a fact that treatment effects on different disease targets like beta-secretase could be reproduced in human clinical trial, but biochemical changes did not result in functional improvements. It seems obvious that cognitive changes that were shown in rats and mice as a consequence of the genetic manipulation or the lesion are most likely not the cause of cognitive disturbance in humans. This lack of correlation leads to wrong conclusions in selection of new treatments for clinical testing. So the selection of models was already critical, but in addition