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Biomarker and long-term effects of cholinesterase inhibitors in Alzheimer's disease and MCI
P116
Poster Presentations: P1
they don’t typically capture inherent brain physiology and dynamic processes. The present study extends an activated EEG medical device for the physiological assessment of brain health looking at multivariate classifiers. Methods: Recent advances in wireless electroencephalography hardware have enabled the development of a novel activated EEG system (MindReader TM) to physiologically focus the assessment of brain health to various sensory circuits and cognitive tasks. The MindReader assesses brain function while actively stimulating the subject with various stimuli. Last year at AAIC Paris, BCI reported univariate results which replicated and extended the published EEG diagnostic literature. This year, multi-variate predictive statistical models were built and tested in JMP Pro v9 from SAS to assess clinical performance to accuracy classify mild AD from Control. Tree based methods (e.g. Random Forests), discriminant analysis (e.g. linear), 2-layer Neural Networks and other techniques were run on our data table of n ¼ 10 AD vs n ¼ 13 Controls. Results: Several models showed interesting 2, 3, 4 and 5-marker classifiers selected from a list of over 150 published or proprietary EEG biomarker candidates for each of m ¼ 16 tasks per subject. Clinical performance ranged from mediocre (60 % sensitivity, 60% specificity) to modest (75% / 72% respectively). Leave one out internal cross-validation was utilized to more accurately characterize the misclassification rate, while the best model will be presented, built on the entire data set. Conclusions: A physiologically focused battery of activated EEG tasks is able to probe elements of brain circuits not presently assessed with standard resting state (Eyes Open or Eyes Closed) quantitative EEG. The MindReader offers a novel alternative to rapidly, portably and non-invasively assess brain health and function. Multi-variate predictive models offer an opportunity to enhance classifier performance, although further work is required to develop the necessary activated EEG signatures to map the brain for its physiological defects.
P1-025
GENE EXPRESSION ANALYSIS IN THE POSTMORTEM BRAINS CLASSIFIED BY BRAAK NFT-SP STAGING
Background: Patients who present with Alzheimer’s disease (AD) or mild cognitive impairment (MCI) due to AD have life expectancies of many years. However, very little controlled data on the effects of ChEIs beyond one year are available. Therefore, randomized, controlled studies of biomarkers, and long-term placebo-controlled studies of ChEIs in AD and MCI were sought. Methods: A literature review identified randomized biomarker or long-term placebo-controlled studies of ChEIs in AD or MCI. Results: In a 13-week, randomized study of the ChEIs in 63 AD patients, donepezil markedly elevated CSF acetylcholinesterase enzyme (+215.2%). (Nordberg 2009) Galantamine increased AChE to slightly above the normal range (+51.2%) Rivastigmine produced a decrease (-21.8%). Donepezil significantly increased CSF tau and ptau from baseline. Galantamine increased Ab1-42 and decreased ptau, both relative to rivastigmine (see figure). Galantamine reduced whole brain atrophy in MCI patients by 33% at two years. (Scheltens 2004) It is not approved or recommended for MCI. Donepezil did not significantly affect whole brain volume at 2.5 years, nor did rivastigmine up to four years. (Jack 2008, Feldman 2007)In randomized, placebo-controlled MCI studies, the ratios of donepezil-treated to placebo-treated patients converting to AD were: .12, .67, .88, 1.75, 1.33, 2.2 at 6, 12, 18, 24, 30 and 36 months. (Petersen 2004) The corresponding ratios for galantamine (24 months) were: .73, .81, .69, .83, and for rivastigmine (48 months): 1.0, .41, 1.53, .66, .91, 1.65, .87, 1.0. (Winblad 2008, Feldman 2007) In controlled two-year studies in AD, donepezil produced a slight cognitive effect (AD Collaborative Group 2004); rivastigmine and donepezil behaved similarly. (Bullock 2005) Conclusions: 1. Donepezil markedly elevates AChE, and increases biomarkers of neurodegeneration, tau and ptau. An initial decrease in MCI conversions becomes an increase by two years. Excess AChE promotes the amyloid cascade, perhaps explaining the change of effect. (Rees 2003) 2. Galantamine restores AChE, which supports hippocampal neurite formation, to near normal from decreased levels in AD. (Day, 2002) Galantamine increases Aß1-42 towards normal and decreases ptau, both relative to rivastigmine. Effects are steady over two years. 3. Galantamine slows the rate of brain atrophy in MCI. Donepezil and rivastigmine do not.
Akinori Miyashita1, Yuko Saito2, Hiroyuki Hatsuta3, Tamao Tsukie4, Akihiro Nakaya5, Shigeo Murayama3, Yasuo Ihara6, Ryozo Kuwano1, 1 Brain Research Institute, Niigata University, Niigata, Japan; 2National Center Hospital of Neurology and Psychiatry, Kodaira, Japan; 3Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku, Japan; 4Research Association for Biotechnology, Minato-ku, Japan; 5 Center for Transdisciplinary Research, Niigata University, Niigata, Japan; 6 Doshisha University, Kizugawa, Japan. Background: Alzheimer’s disease (AD) is the most common form of dementia in the elderly. Molecular mechanisms underlying the progression of AD neuropathological hallmarks, senile plaques (SP) and neurofibrillary tangles (NFT), in the brain remains to be resolved. The objective of this study is to identify exons/genes associated with Braak SP-NFT stage criteria. Results: The genotypic distribution of the APOE is as follows: E23 ¼ 4, E33 ¼ 55, E34 ¼ 9, E44 ¼ 3. In three brain regions, there were no significant differences of mean RIN values among Braak SP-NFT stages. No correlation between PMI (post mortem interval) and RIN was observed. We found that transcription levels of genes showed the significant association with Braak SP-NFT stage criteria. Conclusions: We now focus on genes differentially expressed among Braak SP-NFT staging depending on the brain regions. Several genes responsible for progression of neuropathological changes in AD brain could be elucidated through gene expression profiling.
P1-026
BIOMARKER AND LONG-TERM EFFECTS OF CHOLINESTERASE INHIBITORS IN ALZHEIMER’S DISEASE AND MCI
Bonnie Davis, Synaptec Inc, Cold Spring Harbor, New York, United States.
Figure 1. In a 3 mo head-to-head study in AD, galantamine improved CSF ptau and Ab1-42 vs rivastigmine. Donepezil worsened tau and ptau.
P1-027
ASTROCYTE-DERIVED PROTEINS IN THE CEREBROSPINAL FLUID AS BIOMARKERS FOR THE PATHOBIOLOGICAL STAGING OF ALZHEIMER’S DISEASE
Carola Schipke, Arne Fesche, Brigitte Haas, Isabella Heuser, Oliver Peters, Charite Universit€ats-Medizin Berlin, Berlin, Germany. Background: The quantitative analysis of biomarker proteins in the cerebrospinal fluid (CSF) substantiates the clinical diagnosis of AD
Poster Presentations: P1
they don’t typically capture inherent brain physiology and dynamic processes. The present study extends an activated EEG medical device for the physiological assessment of brain health looking at multivariate classifiers. Methods: Recent advances in wireless electroencephalography hardware have enabled the development of a novel activated EEG system (MindReader TM) to physiologically focus the assessment of brain health to various sensory circuits and cognitive tasks. The MindReader assesses brain function while actively stimulating the subject with various stimuli. Last year at AAIC Paris, BCI reported univariate results which replicated and extended the published EEG diagnostic literature. This year, multi-variate predictive statistical models were built and tested in JMP Pro v9 from SAS to assess clinical performance to accuracy classify mild AD from Control. Tree based methods (e.g. Random Forests), discriminant analysis (e.g. linear), 2-layer Neural Networks and other techniques were run on our data table of n ¼ 10 AD vs n ¼ 13 Controls. Results: Several models showed interesting 2, 3, 4 and 5-marker classifiers selected from a list of over 150 published or proprietary EEG biomarker candidates for each of m ¼ 16 tasks per subject. Clinical performance ranged from mediocre (60 % sensitivity, 60% specificity) to modest (75% / 72% respectively). Leave one out internal cross-validation was utilized to more accurately characterize the misclassification rate, while the best model will be presented, built on the entire data set. Conclusions: A physiologically focused battery of activated EEG tasks is able to probe elements of brain circuits not presently assessed with standard resting state (Eyes Open or Eyes Closed) quantitative EEG. The MindReader offers a novel alternative to rapidly, portably and non-invasively assess brain health and function. Multi-variate predictive models offer an opportunity to enhance classifier performance, although further work is required to develop the necessary activated EEG signatures to map the brain for its physiological defects.
P1-025
GENE EXPRESSION ANALYSIS IN THE POSTMORTEM BRAINS CLASSIFIED BY BRAAK NFT-SP STAGING
Background: Patients who present with Alzheimer’s disease (AD) or mild cognitive impairment (MCI) due to AD have life expectancies of many years. However, very little controlled data on the effects of ChEIs beyond one year are available. Therefore, randomized, controlled studies of biomarkers, and long-term placebo-controlled studies of ChEIs in AD and MCI were sought. Methods: A literature review identified randomized biomarker or long-term placebo-controlled studies of ChEIs in AD or MCI. Results: In a 13-week, randomized study of the ChEIs in 63 AD patients, donepezil markedly elevated CSF acetylcholinesterase enzyme (+215.2%). (Nordberg 2009) Galantamine increased AChE to slightly above the normal range (+51.2%) Rivastigmine produced a decrease (-21.8%). Donepezil significantly increased CSF tau and ptau from baseline. Galantamine increased Ab1-42 and decreased ptau, both relative to rivastigmine (see figure). Galantamine reduced whole brain atrophy in MCI patients by 33% at two years. (Scheltens 2004) It is not approved or recommended for MCI. Donepezil did not significantly affect whole brain volume at 2.5 years, nor did rivastigmine up to four years. (Jack 2008, Feldman 2007)In randomized, placebo-controlled MCI studies, the ratios of donepezil-treated to placebo-treated patients converting to AD were: .12, .67, .88, 1.75, 1.33, 2.2 at 6, 12, 18, 24, 30 and 36 months. (Petersen 2004) The corresponding ratios for galantamine (24 months) were: .73, .81, .69, .83, and for rivastigmine (48 months): 1.0, .41, 1.53, .66, .91, 1.65, .87, 1.0. (Winblad 2008, Feldman 2007) In controlled two-year studies in AD, donepezil produced a slight cognitive effect (AD Collaborative Group 2004); rivastigmine and donepezil behaved similarly. (Bullock 2005) Conclusions: 1. Donepezil markedly elevates AChE, and increases biomarkers of neurodegeneration, tau and ptau. An initial decrease in MCI conversions becomes an increase by two years. Excess AChE promotes the amyloid cascade, perhaps explaining the change of effect. (Rees 2003) 2. Galantamine restores AChE, which supports hippocampal neurite formation, to near normal from decreased levels in AD. (Day, 2002) Galantamine increases Aß1-42 towards normal and decreases ptau, both relative to rivastigmine. Effects are steady over two years. 3. Galantamine slows the rate of brain atrophy in MCI. Donepezil and rivastigmine do not.
Akinori Miyashita1, Yuko Saito2, Hiroyuki Hatsuta3, Tamao Tsukie4, Akihiro Nakaya5, Shigeo Murayama3, Yasuo Ihara6, Ryozo Kuwano1, 1 Brain Research Institute, Niigata University, Niigata, Japan; 2National Center Hospital of Neurology and Psychiatry, Kodaira, Japan; 3Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku, Japan; 4Research Association for Biotechnology, Minato-ku, Japan; 5 Center for Transdisciplinary Research, Niigata University, Niigata, Japan; 6 Doshisha University, Kizugawa, Japan. Background: Alzheimer’s disease (AD) is the most common form of dementia in the elderly. Molecular mechanisms underlying the progression of AD neuropathological hallmarks, senile plaques (SP) and neurofibrillary tangles (NFT), in the brain remains to be resolved. The objective of this study is to identify exons/genes associated with Braak SP-NFT stage criteria. Results: The genotypic distribution of the APOE is as follows: E23 ¼ 4, E33 ¼ 55, E34 ¼ 9, E44 ¼ 3. In three brain regions, there were no significant differences of mean RIN values among Braak SP-NFT stages. No correlation between PMI (post mortem interval) and RIN was observed. We found that transcription levels of genes showed the significant association with Braak SP-NFT stage criteria. Conclusions: We now focus on genes differentially expressed among Braak SP-NFT staging depending on the brain regions. Several genes responsible for progression of neuropathological changes in AD brain could be elucidated through gene expression profiling.
P1-026
BIOMARKER AND LONG-TERM EFFECTS OF CHOLINESTERASE INHIBITORS IN ALZHEIMER’S DISEASE AND MCI
Bonnie Davis, Synaptec Inc, Cold Spring Harbor, New York, United States.
Figure 1. In a 3 mo head-to-head study in AD, galantamine improved CSF ptau and Ab1-42 vs rivastigmine. Donepezil worsened tau and ptau.
P1-027
ASTROCYTE-DERIVED PROTEINS IN THE CEREBROSPINAL FLUID AS BIOMARKERS FOR THE PATHOBIOLOGICAL STAGING OF ALZHEIMER’S DISEASE
Carola Schipke, Arne Fesche, Brigitte Haas, Isabella Heuser, Oliver Peters, Charite Universit€ats-Medizin Berlin, Berlin, Germany. Background: The quantitative analysis of biomarker proteins in the cerebrospinal fluid (CSF) substantiates the clinical diagnosis of AD