- Email: [email protected]
Why did animal models fail to show the right way to Alzheimer Therapy?
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
S26
Abstracts / Neurobiology of Aging 35 (2014) S1eS27
neglecting important features of particular mouse strains was also often done. Experiments were not performed in a comparable way to clinical research and unblinded investigations, using small numbers of animals lacking statistical power calculation have the additional risk of false positive data, that were sometimes over-interpreted, especially when they fitted in to the expected pharmcodynamic action of the drug. At the same time it must be speculated that there is significant underreporting and even neglect of negative findings. In the meanwhile improved models are available, also considering important factors like general aging and related co-morbitidy, but so far clinical validation of drugs tested in these systems is missing. So the missing predictive value of the existing AD-models is most likely a combination of choosing lesions (genetic or induced) not relevant for the human disorder and not optimized study design. Keywords. Transgenic mice, Amyloid, Tau protein
TAURX GLOBAL PHASE 3 TRIAL IN ALZHEIMER’S DISEASE WITH TAU AGGREGATION INHIBITOR LMTX Claude M. Wischik, C.R. Harrington, J.M.D. Storey. University of Aberdeen, Aberdeen, Scotland, UK. E-mail: [email protected] There have been 19 phase2/3 clinical trial failures in 15,000 AD subjects to date, all aiming to reduce amyloid pathology. The tau theory has offered an entirely viable alternative conceptual framework, largely ignored for the last 20 years. The filaments of the Alzheimer neurofibrillary tangle are made of a truncated fragment from the repeat domain of tau. This truncated fragment can catalyse the conversion of normal soluble tau into aggregated oligomeric and fibrillary forms which, in turn, can infect neighbouring neurons. Initiation of tau aggregation requires its binding to a non-specific substrate to expose a high affinity tau-tau binding domain and is self-propagating thereafter. The initiating complex is most likely formed as a consequence of age-related degradation of endosomal-lysosomal processing (ELP) of neuronal proteins, particularly of membrane proteins from mitochondria. Tau pathology begins in the late 40s and affects 50% of the population over the age of 45. Unlike amyloid load, tau pathology is highly correlated with cognitive decline in post-mortem epidemiological studies and with FDG-PET imaging deficits, correlations also confirmed with new tau-selective PET ligands. Methylthioninium (MT), the first identified Tau Aggregation Inhibitor (TAI), reverses the proteolytic stability of the tau oligomers/filaments, facilitates their proteolytic clearance and reduces the load of tau pathology in transgenic tau mouse models. A phase 2 clinical trial in 321 subjects with mild/moderate AD demonstrated a reduction of 85% 30% in the rate of disease progression as measured by ADAS-cog over 12 months and prevented progression of functional imaging deficits. The chloride salt of oxidized MT (MTC) has dose-dependent pharmaceutical limitations. We have developed a superior stabilized reduced version of the molecule (leuco-MT, LMTX) that has greater tolerability and better absorption at higher doses. Two global phase 3 trials are currently underway in 22 countries. We expect recruitment of the 1,500 subjects in these trials to be complete by 3rd quarter of 2014, with first data read-out in 2016. Keywords. Tau, Methylthioninium, Alzheimer’s disease
the reaction of MAO. We have synthesized several multi target non-toxic, brain permeable iron chelator drugs, M-30 and HLA-20, possessing propargyl MAO inhibitory moiety, with neuroprotective and neurorestorative activities. These drugs possess antiapoptotic, pro-survival neurorescue effects, induction of neuronal differentiation and regulation of amyloid precursor protein (APP) and b-amyloid (Ab) levels. They induce the outgrowth of neuritis in neuronal cell cultures, trigger cell cycle arrest in G0/G1 phase and enhance the expression of growth associated protein-43, HIF (Hypoxia Inducing Factor) and increase brain levels BDNF, GDNF, VGEF and erythropoietin. This has been shown to be associated with the inhibition of iron dependent prolyl-4-hydroxylase, that regulates HIF. Both M30 and HLA-20 process APP via activation of alpha secretase. They possess neurorestorative activity in in vivo models of Parkinson’s disease and restore the cognitive deficit in APP/PSI double transgenic mice and the streptozotocin (STZ) models of AD. The dual control of mitochondrial biogenesis and energy metabolism is regulated by silent information regulator-1 and -3 (SIRT1 and SIRT3). The peroxisome proliferator activated receptor g co-activator 1a (PGC-1a) is a transcriptional co-activator that is a central inducer of mitochondrial biogenesis in cells. SIRT1 is necessary for HIF-1a protein accumulation and activation of HIF-1 target genes and activates PGC-1a-mediated transcription of nuclear factor (Tfam) and mitochondrial genes encoding for proteins promoting mitochondria proliferation, We have show that M30 and HLA-20 activate SIRT1, PGC-1a, and Tfam in cell cultures and consider them as a novel therapeutic approach for neurodegenerative disorders. Keywords. Neuroprotection, Neurorestoration, Mitochondria biogenesis
NON-PHARMACOLOGICAL DECLINE
INTERVENTION
FOR
MEMORY
Orazio Zanetti. IRCCS Centro S.Giovanni di Dio Fatebenefratelli, Brescia, Italy. E-mail: [email protected] Non-pharmacological intervention of memory difficulties in patients with brain damage and neurodegenerative disorders has gained much attention in recent years. The two main reasons that explain this growing interest in memory rehabilitation are the limited efficacy of current drug therapies and the plasticity of the human brain. The Cochrane Library concluded a recent review stating that “there was consistent evidence from multiple trials that cognitive stimulation programmes benefit cognition in people with mild to moderate dementia over and above any medication effects. However, the trials were of variable quality with small sample sizes and only limited details of the randomisation method were apparent in a number of the trials. Other outcomes need more exploration but improvements in self-reported quality of life and well-being were promising.” Moreover, several studies have reported enhanced cognitive performance in patients with neurological disease, following non-invasive brain stimulation [i.e. repetitive transcranial magnetic stimulation and tran-scranial direct current stimulation to specific cortical areas] with particular regard to cognitive rehabilitation interventions focused on memory and non-invasive brain stimulation. Reviewed data suggest that in patients with memory deficits due to mild cognitive impairment or Alzheimer’s disease, memory intervention therapy could lead to performance improvements. Keywords. Alzheimer’s disease, Cognitive stimulation therapy, Transcranial magnetic stimulation
DESIGNED MULTI FUNCTIONAL DRUGS TARGETING NEUROPROTECTION, NEURORESTORATION AND MITOCHONDRIAL BIOGENESIS VIA ACTIVATION OF HIF1a, SIRT1, PGC-1a AND TFAM Moussa B.H. Youdim. Technion-Rappaport Familty Faculty of Medicine, Eve Topf Center, Haifa, Israel. E-mail: [email protected] Novel therapeutic approaches for the treatment of Alzheimer’s disease (AD) comprise drug candidates designed specifically to act on multiple CNS targets, rather than a single “receptor” as has been done with cholinesterase inhibitors. Major pathology of AD is the accumulation of iron in nucleus basilus, dentate gyrus, amyloid plaques, and tangles and increase in monoamine oxidase (MAO). The iron contributes to the onset of oxidative stress and glutaminergic excitotoxicity via interaction with hydrogen peroxide generated by
ACUTE CARE UNITS FOR ALZHEIMER PATIENTS Dina Zekry, F. Herrmann, P. Gattelet, Y. Registe-Rameau, G. Gold. Geneva University Hospitals and University of Geneva, Thonex, Switzerland. E-mail: [email protected] Patients with behavioral and psychological symptoms of dementia (BPSD) due to a concomitant acute somatic disease are at risk of not being adequately treated in respect to all their problems either in a somatic or in a psychiatric setting. This also results in frequent and often repetitive transfers between different departments. The need for new models of care for patients with dementia hospitalized for somatic disease concomitant with BPSD has led to the development of acute care units for Alzheimer patients. The main target of these units is an improvement
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
S26
Abstracts / Neurobiology of Aging 35 (2014) S1eS27
neglecting important features of particular mouse strains was also often done. Experiments were not performed in a comparable way to clinical research and unblinded investigations, using small numbers of animals lacking statistical power calculation have the additional risk of false positive data, that were sometimes over-interpreted, especially when they fitted in to the expected pharmcodynamic action of the drug. At the same time it must be speculated that there is significant underreporting and even neglect of negative findings. In the meanwhile improved models are available, also considering important factors like general aging and related co-morbitidy, but so far clinical validation of drugs tested in these systems is missing. So the missing predictive value of the existing AD-models is most likely a combination of choosing lesions (genetic or induced) not relevant for the human disorder and not optimized study design. Keywords. Transgenic mice, Amyloid, Tau protein
TAURX GLOBAL PHASE 3 TRIAL IN ALZHEIMER’S DISEASE WITH TAU AGGREGATION INHIBITOR LMTX Claude M. Wischik, C.R. Harrington, J.M.D. Storey. University of Aberdeen, Aberdeen, Scotland, UK. E-mail: [email protected] There have been 19 phase2/3 clinical trial failures in 15,000 AD subjects to date, all aiming to reduce amyloid pathology. The tau theory has offered an entirely viable alternative conceptual framework, largely ignored for the last 20 years. The filaments of the Alzheimer neurofibrillary tangle are made of a truncated fragment from the repeat domain of tau. This truncated fragment can catalyse the conversion of normal soluble tau into aggregated oligomeric and fibrillary forms which, in turn, can infect neighbouring neurons. Initiation of tau aggregation requires its binding to a non-specific substrate to expose a high affinity tau-tau binding domain and is self-propagating thereafter. The initiating complex is most likely formed as a consequence of age-related degradation of endosomal-lysosomal processing (ELP) of neuronal proteins, particularly of membrane proteins from mitochondria. Tau pathology begins in the late 40s and affects 50% of the population over the age of 45. Unlike amyloid load, tau pathology is highly correlated with cognitive decline in post-mortem epidemiological studies and with FDG-PET imaging deficits, correlations also confirmed with new tau-selective PET ligands. Methylthioninium (MT), the first identified Tau Aggregation Inhibitor (TAI), reverses the proteolytic stability of the tau oligomers/filaments, facilitates their proteolytic clearance and reduces the load of tau pathology in transgenic tau mouse models. A phase 2 clinical trial in 321 subjects with mild/moderate AD demonstrated a reduction of 85% 30% in the rate of disease progression as measured by ADAS-cog over 12 months and prevented progression of functional imaging deficits. The chloride salt of oxidized MT (MTC) has dose-dependent pharmaceutical limitations. We have developed a superior stabilized reduced version of the molecule (leuco-MT, LMTX) that has greater tolerability and better absorption at higher doses. Two global phase 3 trials are currently underway in 22 countries. We expect recruitment of the 1,500 subjects in these trials to be complete by 3rd quarter of 2014, with first data read-out in 2016. Keywords. Tau, Methylthioninium, Alzheimer’s disease
the reaction of MAO. We have synthesized several multi target non-toxic, brain permeable iron chelator drugs, M-30 and HLA-20, possessing propargyl MAO inhibitory moiety, with neuroprotective and neurorestorative activities. These drugs possess antiapoptotic, pro-survival neurorescue effects, induction of neuronal differentiation and regulation of amyloid precursor protein (APP) and b-amyloid (Ab) levels. They induce the outgrowth of neuritis in neuronal cell cultures, trigger cell cycle arrest in G0/G1 phase and enhance the expression of growth associated protein-43, HIF (Hypoxia Inducing Factor) and increase brain levels BDNF, GDNF, VGEF and erythropoietin. This has been shown to be associated with the inhibition of iron dependent prolyl-4-hydroxylase, that regulates HIF. Both M30 and HLA-20 process APP via activation of alpha secretase. They possess neurorestorative activity in in vivo models of Parkinson’s disease and restore the cognitive deficit in APP/PSI double transgenic mice and the streptozotocin (STZ) models of AD. The dual control of mitochondrial biogenesis and energy metabolism is regulated by silent information regulator-1 and -3 (SIRT1 and SIRT3). The peroxisome proliferator activated receptor g co-activator 1a (PGC-1a) is a transcriptional co-activator that is a central inducer of mitochondrial biogenesis in cells. SIRT1 is necessary for HIF-1a protein accumulation and activation of HIF-1 target genes and activates PGC-1a-mediated transcription of nuclear factor (Tfam) and mitochondrial genes encoding for proteins promoting mitochondria proliferation, We have show that M30 and HLA-20 activate SIRT1, PGC-1a, and Tfam in cell cultures and consider them as a novel therapeutic approach for neurodegenerative disorders. Keywords. Neuroprotection, Neurorestoration, Mitochondria biogenesis
NON-PHARMACOLOGICAL DECLINE
INTERVENTION
FOR
MEMORY
Orazio Zanetti. IRCCS Centro S.Giovanni di Dio Fatebenefratelli, Brescia, Italy. E-mail: [email protected] Non-pharmacological intervention of memory difficulties in patients with brain damage and neurodegenerative disorders has gained much attention in recent years. The two main reasons that explain this growing interest in memory rehabilitation are the limited efficacy of current drug therapies and the plasticity of the human brain. The Cochrane Library concluded a recent review stating that “there was consistent evidence from multiple trials that cognitive stimulation programmes benefit cognition in people with mild to moderate dementia over and above any medication effects. However, the trials were of variable quality with small sample sizes and only limited details of the randomisation method were apparent in a number of the trials. Other outcomes need more exploration but improvements in self-reported quality of life and well-being were promising.” Moreover, several studies have reported enhanced cognitive performance in patients with neurological disease, following non-invasive brain stimulation [i.e. repetitive transcranial magnetic stimulation and tran-scranial direct current stimulation to specific cortical areas] with particular regard to cognitive rehabilitation interventions focused on memory and non-invasive brain stimulation. Reviewed data suggest that in patients with memory deficits due to mild cognitive impairment or Alzheimer’s disease, memory intervention therapy could lead to performance improvements. Keywords. Alzheimer’s disease, Cognitive stimulation therapy, Transcranial magnetic stimulation
DESIGNED MULTI FUNCTIONAL DRUGS TARGETING NEUROPROTECTION, NEURORESTORATION AND MITOCHONDRIAL BIOGENESIS VIA ACTIVATION OF HIF1a, SIRT1, PGC-1a AND TFAM Moussa B.H. Youdim. Technion-Rappaport Familty Faculty of Medicine, Eve Topf Center, Haifa, Israel. E-mail: [email protected] Novel therapeutic approaches for the treatment of Alzheimer’s disease (AD) comprise drug candidates designed specifically to act on multiple CNS targets, rather than a single “receptor” as has been done with cholinesterase inhibitors. Major pathology of AD is the accumulation of iron in nucleus basilus, dentate gyrus, amyloid plaques, and tangles and increase in monoamine oxidase (MAO). The iron contributes to the onset of oxidative stress and glutaminergic excitotoxicity via interaction with hydrogen peroxide generated by
ACUTE CARE UNITS FOR ALZHEIMER PATIENTS Dina Zekry, F. Herrmann, P. Gattelet, Y. Registe-Rameau, G. Gold. Geneva University Hospitals and University of Geneva, Thonex, Switzerland. E-mail: [email protected] Patients with behavioral and psychological symptoms of dementia (BPSD) due to a concomitant acute somatic disease are at risk of not being adequately treated in respect to all their problems either in a somatic or in a psychiatric setting. This also results in frequent and often repetitive transfers between different departments. The need for new models of care for patients with dementia hospitalized for somatic disease concomitant with BPSD has led to the development of acute care units for Alzheimer patients. The main target of these units is an improvement