- Email: [email protected]
Interactions between tau phosphatases and tau kinases in formation of tau hyperphosphorylation in Alzheimer's disease
Symposia S2-01: Disease Mechanisms: Tau, Taupathies fractionation were employed to examine the subcellular localization of hyperphosphorylated tau in the spinal cord and brain of JNPL3 mice and in AD brain. Results: A significant higher number of contacts between rough endoplasmic reticulum (RER) membranes and mitochondria was observed in motor neurons of the spinal cord in JNLP3 mice than in wild-type mice. This correlated with a preferential increase of the amount of tau at the surface of RER membranes but not at the surface of mitochondria as revealed by tau immunogold labeling in motor neurons where insoluble tau filaments form. Using a subcellular fractionation procedure, an increased amount of phosphorylated tau was noted in the RM (rough microsomes) subfraction where the RER marker, ribophorin was enriched in brain of JNPL3 mice. A similar observation was noted in subfractions isolated from AD brain. The association of hyperphosphorylated tau with ER membranes was confirmed by double immunogold labeling of the subfraction enriched in ER membranes isolated from AD brain. Conclusions: The interaction between RER/mitochondria regulates calcium homeostasis which is perturbed in AD. The present study suggests that the increased number of contacts between RER membranes and mitochondria that could result from the accumulation of tau at the surface of RER membranes might contribute to tau-induced neurodegeneration by perturbing calcium homeostasis.
anti-apoptotic mechanisms in Alzheimer disease. Methods: We used brain injection and primary hippoacampal neuron cultures, and as wll as different iamging techniques for the study. Results: To study the role of tau phosphorylation in d neurodevelopment. We found that the immature neurons, identified by doublecortin (DCX) and neuroD, were labeled only by phosphorylated tau (p-tau) but not the unphosphorylated tau. During postnatal development, a correlated expression/localization of DCX and neuroD with p-tau was observed in dentate gyrus of the rat hippocampus, and co-localization of the p-tau with DCX was also detected in the hippocampus of AD patients. We also found that activating glycogen synthase kinase-3 (GSK-3), a crucial tau kinase, induced correlatively increased expression of the immature neuron markers and tau hyperphosphorylation, and the enhanced neurogenesis was due to an increased proliferation of the newborn neurons. Finally, severe deficit of neurogenesis was found in mice with tau knockout and activation of GSK-3 did not improve the deficits. Conclusions: From these findings, we conclude that tau phosphorylation plays an essential role in adult hippocampal neurogenesis, which may underlie the enhanced neurogenesis observed in AD brain.
S2-01-04 S2-01-02
TAU VACCINE: ACTIVE IMMUNIZATION WITH MISFOLDED TAU PROTEIN ATTENUATES TAU PATHOLOGY IN THE TRANSGENIC RAT MODEL OF TAUOPATHY
Michal Novak, Axon Neuroscience, Vienna, Austria. Contact e-mail: [email protected] Background: Hyperphosphorylation and truncation, the major pathological alterations of tau, are present both in Alzheimer’s disease (AD) and in non-AD tauopathies. In order to analyze the role of misfolded tau protein in the neurodegenerative cascade we generated a rat model of tauopathy. We showed that non-mutated truncated tau derived from sporadic Alzheimer’s disease is able to induce and drive neurofibrillary degeneration in rats when expressed as transgene. Methods: Transgenic rat were immunized with recombinant misfolded truncated tau before the onset of neurobehavioral alterations. Improvement of neurobehavioral functions was monitored by multi-test battery with novel sensitive scoring system - NeuroScale. Sarcosyl soluble and insoluble tau were detected by Western-blot analysis. Phosphorylated tau in cerebrospinal fluid (CSF) was detected by ELISA P181 (Innogenetics). Neurofibrillary pathology was identified by immunohistochemistry using phosphorylation dependent anti-tau antibodies. Results: Immunization with misfolded truncated tau protein resulted in statistically significant delay of the progressive neurobehavioral impairment of transgenic rats. Moreover immunotherapy prevented the development of neurofibrillary tangles and formation of sarcosyl insoluble tau complexes. Immunization significantly reduced the levels of the phosphorylated as well as non-phosphorylated soluble misfolded tau protein in the brain. Conclusions: The ability of the misfolded tau based active immunotherapy to delay the onset of severe sensorimotor deficits in transgenic rat model, without obvious harmful side effects, would predict a favourable scenario for therapeutic intervention in Alzheimer’s disease and related neurodegenerative tauopathies.
S2-01-03
REGULATION OF GSK-3 BY SETa AND ITS EFFECT ON ABNORMAL HYPERPHOSPHORYLATION OF TAU
Jian-Zhi Wang, Tongji Medical College, HUST, Wuhan, China. Contact e-mail: [email protected] Background: As a major proteinous component of neurofibrillary tangles, the phosphorylation of tau has been demonstrated to be an early event in neurodegeneration. We have recently proposed that neurodegeneration is the consequence of an aborted apoptosis based on the discovery of several
P93
ASSOCIATION BETWEEN CSF PHOSPHORYLATED TAU AND RISK FACTORS OF ALZHEIMER’S DISEASE
Michael Ewers, Department of Psychiatry, Trinity College, Dublin, Ireland. Contact e-mail: [email protected] Background: Neurofibrillary changes are a core histochemical neuropathology in Alzheimer’s disease (AD), and the concentration of phosphorylated tau (p-tau) and total tau in the cerebrospinal fluid (CSF) as in vivo biological markers of neurofibrillary pathology are increased in patients AD and mild cognitive impairment (MCI). However, it is less well known whether neurofibrillary changes are related to risk factors of AD. Here we assess the association of metabolic (body weight) and genetic risk factors in relation to changes in CSF-tau and p-tau181 in AD and MCI. Methods: Changes in body mass index (BMI) are known to be related to core Abeta and neurofibrillary pathology in the brain as assessed in post-mortem studies so far. In order to examine whether BMI is related to CSF-levels of tau, we examined in a total of 56 patients diagnosed with probable AD according to the NINCDS-ADRDA criteria and 43 healthy controls (HC) the CSF-concentration of total tau, p-tau181, and beta amyloid (Ab1-42). In a larger sample of AD and amnestic MCI subjects, the association between primary genetic risk factors including polymorphisms such as CALHM1, SORLA, and (ApoE) genotype were assessed in relation to differences in the concentration of the CSF-concentration of tau and p-tau181. Results: A decrease in BMI was associated with increased CSF-levels of p-tau181 (p ¼ 0.01), controlled for age, gender, MMSE, years of education, and ApoE genotype. Similarly, higher CSF-concentration of total tau were associated with a decrease in BMI (p ¼ 0.001). The concentration of Ab1-42 in CSF was not related to BMI (p > 0.05). The direct association between genetic polymorphisms including ApoE genotype, CALHM1, SORLA and the CSF-concentration of ptau181 and tau in subjects with AD and MCI will be discussed. Conclusions: Lower BMI is indicative of higher CSF-concentration of p-tau181 and total tau in AD, consistent with post-mortem findings. Future studies need to investigate whether such changes in BMI are related to a larger metabolic syndrome including inflammation and glucose metabolism in AD. The determination of CSF-concentration of p-tau provides an in vivo measure to assess whether increased genetic risk of AD is associated with neurofibrillary pathology.
S2-01-05
INTERACTIONS BETWEEN TAU PHOSPHATASES AND TAU KINASES IN FORMATION OF TAU HYPERPHOSPHORYLATION IN ALZHEIMER’S DISEASE
Jin Jing Pei, Karolinska Institutet, Huddinge, Sweden. Contact e-mail: [email protected]
Symposia S2-02: Diagnosis: Biomarkers
P94
Background: The abnormal hyperphosphorylation of tau is one of the key puzzles in Alzheimer’s disease brain. It is believed that this process is caused by an imbalanced activity of protein kinases and protein phosphatases. Methods: Based on the data generated from post-mortem human brains, cellular and in vivo models of AD from our and other groups, the recent achievements on the possible synergistic role of protein phosphatase 2A and protein kinases p70S6K, PKB, GSK3, JNK and /or ERK towards tau is reviewed in this presentation. Conclusions: Multiple drug targets should be addressed at the same time in order to efficiently treat the disease.
S2-01-06
ROLE OF PP2A METHYLATION PATHWAYS IN TAU REGULATION
Estelle Sontag, University of Newcastle, Callaghan, NSW, Australia. Contact e-mail: [email protected] Background: The accumulation of filamentous lesions containing phosphorylated tau is a neuropathological hallmark of all tauopathies, including AD and frontotemporal dementia. Notably, the protein phosphatase 2A (PP2A) holoenzyme containing the PR55/Ba subunit (PP2A/Ba) specifically binds to tau and is a major tau phosphatase in vivo. PP2A catalytic C subunit is methylated on the Leu-309 residue by a dedicated leucine carboxyl methyltransferase (LCMT1), and demethylated by a specific protein phosphatase methylesterase (PME-1). This reversible process critically modulates the recruitment of specific regulatory B subunits to the (AC) core enzyme, thereby contributing to the complex regulation of PP2A biogenesis and substrate specificity. Significantly, PP2A methylation promotes the formation of PP2A/Ba. Methods: We have used cultured neuroblastoma cells and mouse models to study the link between one-carbon metabolism, LCMT1-dependent PP2A methylation and the regulation of tau phosphorylation. Results: We have identified a novel mechanism linking LCMT1-mediated PP2A methylation pathways and tau regulation. We have shown that dietary folate deficiency and elevated levels of homocysteine can lead to significant downregulation of LCMT-1 in the mouse brain. As observed in AD autopsy brain tissue, decreased expression levels of LCMT1 in vitro and in vivo correlate with the loss of methylated PP2A and PP2A/Ba, and increased phosphorylation of tau at epitopes found in AD and non-AD tauopathies. We have preliminary evidence suggesting that the disturbance of PP2A methylation pathways could also be triggered in Parkinson’s disease. Conclusions: Our results suggest that counteracting the loss of LCMT1 and PP2A/Ba could represent a novel therapeutic strategy to prevent or slow down tau pathology.
MONDAY, JULY 13, 2009 SYMPOSIA S2-02 DIAGNOSIS: BIOMARKERS S2-02-01
MEASUREMENT OF AMYLOID-BETA PRODUCTION AND CLEARANCE DIRECTLY IN HUMANS
Randall J. Bateman, Washington University, St. Louis, MO, USA. Contact e-mail: [email protected] Background: Production and clearance of central nervous system proteins including amyloid-beta are likely related to Alzheimer’s disease pathophysiology. Techniques to measure this directly in humans has been developed. Methods: Human participants are labeled with a stable isotope amino acid during sampling of blood and cerebrospinal fluid from the CNS. Measurements of labeled and unlabeled CNS proteins over time are made with mass spectrometry. Results: A review of the latest findings of amyloidbeta metabolism and other CNS protein metabolism will be presented. Conclusions: Stable isotope labeling kinetics of CNS proteins in humans are likely to provide practical new information on the pathophysiology of Alzheimer’s disease and the responses to therapeutics which target these proteins.
S2-02-02
THE SWEDISH BRAIN POWER MULTICENTER STUDY: CSF BIOMARKER DATA REPORT
Niklas Mattson, University of Gothenburg, Institute of Neuroscience and Physiology, Go¨teborg, Sweden. Contact e-mail: niklas.mattsson@neuro. gu.se Background: Several studies show that cerebrospinal fluid (CSF) biomarkers have a high diagnostic accuracy for Alzheimer’s disease (AD). Recent studies also show that CSF biomarkers may be useful to identify incipient AD in patients with mild cognitive impairment (MCI), but conclusive large-scale multi-center studies are missing. The objective of this study was to determine the diagnostic accuracy of CSF b-amyloid1-42 (Ab42), total tau protein (T-tau) and tau phosphorylated at position threonine 181 (P-tau) for incipient AD in a large heterogenic group of MCI patients. Methods: The study was designed in accordance with the STARD criteria. Twelve centers in Europe and US participated. Seven hundred fifty subjects with MCI, 529 with AD, and 304 controls were included. MCI subjects were followed for at least two years or until the symptoms had progressed to clinical dementia. Results: During follow-up, 271 MCI patients were diagnosed with AD and 59 with other dementias. MCI patients with incipient AD had lower Ab42 and higher P-tau and T-tau levels than other MCI patients. CSF biomarker levels did not differ between incipient AD patients and AD patients with dementia at baseline. Optimal cut-off levels were defined in the AD with dementia and control groups and tested in the MCI group, where the combination of Ab42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83 % (95% CI 78-88), a specificity of 72 % (95% CI 6876), a positive likelihood ratio of 3.0 (95% CI 2.5-3.4), a negative likelihood ratio of 0.24 (95% CI 0.21-0.28) and an odds ratio of 12.0 (95% CI 7.818.4, p<0.001). Conclusions: This study confirms that CSF Ab42, T-tau and P-tau can identify incipient AD with good accuracy, even in a multicenter setting. These CSF biomarkers may thus be useful as diagnostic tools in memory clinics, and also to enrich clinical MCI trials with incipient AD cases.
S2-02-03
THE ADNI MULTICENTER STUDY: CSF BIOMARKERS DATA REPORT
Leslie M. Shaw, University of Pennsylvania Medical Center, Philadelphia, PA, USA. Contact e-mail: [email protected] Background: The goals of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) biochemical biomarker core include development of standardized biochemical biomarker methods for AD trials and validation of these methods by correlating them with imaging biomarker methods and neuropsychological and behavioral test data from the ADNI cohorts. Methods: Ab1-42, total tau and tau phosphorylated at the threonine 181 position were measured in (a) CSF samples obtained during baseline evaluation of 100 mild AD, 196 mild cognitive impairment (MCI) and 114 elderly cognitively normal (NC) subjects participating in ADNI and in (b) an independent set of 56 autopsy-confirmed AD subjects and 52 age-matched elderly NC using a multicenter-qualified multiplex immunoassay system (Luminex platform and Innogenetics research reagents). Detection of an AD CSF profile for t-tau and Ab1-42 levels in ADNI subjects was achieved using receiver operating characteristic (ROC) cutpoints and logistic regression models derived from the autopsy-confirmed CSF biomarker data. Results: CSF Ab1-42 was the most sensitive biomarker for AD detection in the autopsy-confirmed cohort of pathology-based CSF samples: ROC area under the curve of 0.913 and sensitivity for AD detection (96.4%), negative predictive value (95.2%), specificity for discriminating AD from elderly NC (76.9%), positive predictive value (81.8%) and overall test accuracy of 87%. In the ADNI cohort, a logistic regression model for Ab1-42, t-tau and APOe4 allele count, provided the best assessment delineation of mild AD. An ADlike pathological baseline CSF profile for t-tau/Ab1-42 was detected in 33/ 37 ADNI MCI subjects who converted to probable AD during the first
anti-apoptotic mechanisms in Alzheimer disease. Methods: We used brain injection and primary hippoacampal neuron cultures, and as wll as different iamging techniques for the study. Results: To study the role of tau phosphorylation in d neurodevelopment. We found that the immature neurons, identified by doublecortin (DCX) and neuroD, were labeled only by phosphorylated tau (p-tau) but not the unphosphorylated tau. During postnatal development, a correlated expression/localization of DCX and neuroD with p-tau was observed in dentate gyrus of the rat hippocampus, and co-localization of the p-tau with DCX was also detected in the hippocampus of AD patients. We also found that activating glycogen synthase kinase-3 (GSK-3), a crucial tau kinase, induced correlatively increased expression of the immature neuron markers and tau hyperphosphorylation, and the enhanced neurogenesis was due to an increased proliferation of the newborn neurons. Finally, severe deficit of neurogenesis was found in mice with tau knockout and activation of GSK-3 did not improve the deficits. Conclusions: From these findings, we conclude that tau phosphorylation plays an essential role in adult hippocampal neurogenesis, which may underlie the enhanced neurogenesis observed in AD brain.
S2-01-04 S2-01-02
TAU VACCINE: ACTIVE IMMUNIZATION WITH MISFOLDED TAU PROTEIN ATTENUATES TAU PATHOLOGY IN THE TRANSGENIC RAT MODEL OF TAUOPATHY
Michal Novak, Axon Neuroscience, Vienna, Austria. Contact e-mail: [email protected] Background: Hyperphosphorylation and truncation, the major pathological alterations of tau, are present both in Alzheimer’s disease (AD) and in non-AD tauopathies. In order to analyze the role of misfolded tau protein in the neurodegenerative cascade we generated a rat model of tauopathy. We showed that non-mutated truncated tau derived from sporadic Alzheimer’s disease is able to induce and drive neurofibrillary degeneration in rats when expressed as transgene. Methods: Transgenic rat were immunized with recombinant misfolded truncated tau before the onset of neurobehavioral alterations. Improvement of neurobehavioral functions was monitored by multi-test battery with novel sensitive scoring system - NeuroScale. Sarcosyl soluble and insoluble tau were detected by Western-blot analysis. Phosphorylated tau in cerebrospinal fluid (CSF) was detected by ELISA P181 (Innogenetics). Neurofibrillary pathology was identified by immunohistochemistry using phosphorylation dependent anti-tau antibodies. Results: Immunization with misfolded truncated tau protein resulted in statistically significant delay of the progressive neurobehavioral impairment of transgenic rats. Moreover immunotherapy prevented the development of neurofibrillary tangles and formation of sarcosyl insoluble tau complexes. Immunization significantly reduced the levels of the phosphorylated as well as non-phosphorylated soluble misfolded tau protein in the brain. Conclusions: The ability of the misfolded tau based active immunotherapy to delay the onset of severe sensorimotor deficits in transgenic rat model, without obvious harmful side effects, would predict a favourable scenario for therapeutic intervention in Alzheimer’s disease and related neurodegenerative tauopathies.
S2-01-03
REGULATION OF GSK-3 BY SETa AND ITS EFFECT ON ABNORMAL HYPERPHOSPHORYLATION OF TAU
Jian-Zhi Wang, Tongji Medical College, HUST, Wuhan, China. Contact e-mail: [email protected] Background: As a major proteinous component of neurofibrillary tangles, the phosphorylation of tau has been demonstrated to be an early event in neurodegeneration. We have recently proposed that neurodegeneration is the consequence of an aborted apoptosis based on the discovery of several
P93
ASSOCIATION BETWEEN CSF PHOSPHORYLATED TAU AND RISK FACTORS OF ALZHEIMER’S DISEASE
Michael Ewers, Department of Psychiatry, Trinity College, Dublin, Ireland. Contact e-mail: [email protected] Background: Neurofibrillary changes are a core histochemical neuropathology in Alzheimer’s disease (AD), and the concentration of phosphorylated tau (p-tau) and total tau in the cerebrospinal fluid (CSF) as in vivo biological markers of neurofibrillary pathology are increased in patients AD and mild cognitive impairment (MCI). However, it is less well known whether neurofibrillary changes are related to risk factors of AD. Here we assess the association of metabolic (body weight) and genetic risk factors in relation to changes in CSF-tau and p-tau181 in AD and MCI. Methods: Changes in body mass index (BMI) are known to be related to core Abeta and neurofibrillary pathology in the brain as assessed in post-mortem studies so far. In order to examine whether BMI is related to CSF-levels of tau, we examined in a total of 56 patients diagnosed with probable AD according to the NINCDS-ADRDA criteria and 43 healthy controls (HC) the CSF-concentration of total tau, p-tau181, and beta amyloid (Ab1-42). In a larger sample of AD and amnestic MCI subjects, the association between primary genetic risk factors including polymorphisms such as CALHM1, SORLA, and (ApoE) genotype were assessed in relation to differences in the concentration of the CSF-concentration of tau and p-tau181. Results: A decrease in BMI was associated with increased CSF-levels of p-tau181 (p ¼ 0.01), controlled for age, gender, MMSE, years of education, and ApoE genotype. Similarly, higher CSF-concentration of total tau were associated with a decrease in BMI (p ¼ 0.001). The concentration of Ab1-42 in CSF was not related to BMI (p > 0.05). The direct association between genetic polymorphisms including ApoE genotype, CALHM1, SORLA and the CSF-concentration of ptau181 and tau in subjects with AD and MCI will be discussed. Conclusions: Lower BMI is indicative of higher CSF-concentration of p-tau181 and total tau in AD, consistent with post-mortem findings. Future studies need to investigate whether such changes in BMI are related to a larger metabolic syndrome including inflammation and glucose metabolism in AD. The determination of CSF-concentration of p-tau provides an in vivo measure to assess whether increased genetic risk of AD is associated with neurofibrillary pathology.
S2-01-05
INTERACTIONS BETWEEN TAU PHOSPHATASES AND TAU KINASES IN FORMATION OF TAU HYPERPHOSPHORYLATION IN ALZHEIMER’S DISEASE
Jin Jing Pei, Karolinska Institutet, Huddinge, Sweden. Contact e-mail: [email protected]
Symposia S2-02: Diagnosis: Biomarkers
P94
Background: The abnormal hyperphosphorylation of tau is one of the key puzzles in Alzheimer’s disease brain. It is believed that this process is caused by an imbalanced activity of protein kinases and protein phosphatases. Methods: Based on the data generated from post-mortem human brains, cellular and in vivo models of AD from our and other groups, the recent achievements on the possible synergistic role of protein phosphatase 2A and protein kinases p70S6K, PKB, GSK3, JNK and /or ERK towards tau is reviewed in this presentation. Conclusions: Multiple drug targets should be addressed at the same time in order to efficiently treat the disease.
S2-01-06
ROLE OF PP2A METHYLATION PATHWAYS IN TAU REGULATION
Estelle Sontag, University of Newcastle, Callaghan, NSW, Australia. Contact e-mail: [email protected] Background: The accumulation of filamentous lesions containing phosphorylated tau is a neuropathological hallmark of all tauopathies, including AD and frontotemporal dementia. Notably, the protein phosphatase 2A (PP2A) holoenzyme containing the PR55/Ba subunit (PP2A/Ba) specifically binds to tau and is a major tau phosphatase in vivo. PP2A catalytic C subunit is methylated on the Leu-309 residue by a dedicated leucine carboxyl methyltransferase (LCMT1), and demethylated by a specific protein phosphatase methylesterase (PME-1). This reversible process critically modulates the recruitment of specific regulatory B subunits to the (AC) core enzyme, thereby contributing to the complex regulation of PP2A biogenesis and substrate specificity. Significantly, PP2A methylation promotes the formation of PP2A/Ba. Methods: We have used cultured neuroblastoma cells and mouse models to study the link between one-carbon metabolism, LCMT1-dependent PP2A methylation and the regulation of tau phosphorylation. Results: We have identified a novel mechanism linking LCMT1-mediated PP2A methylation pathways and tau regulation. We have shown that dietary folate deficiency and elevated levels of homocysteine can lead to significant downregulation of LCMT-1 in the mouse brain. As observed in AD autopsy brain tissue, decreased expression levels of LCMT1 in vitro and in vivo correlate with the loss of methylated PP2A and PP2A/Ba, and increased phosphorylation of tau at epitopes found in AD and non-AD tauopathies. We have preliminary evidence suggesting that the disturbance of PP2A methylation pathways could also be triggered in Parkinson’s disease. Conclusions: Our results suggest that counteracting the loss of LCMT1 and PP2A/Ba could represent a novel therapeutic strategy to prevent or slow down tau pathology.
MONDAY, JULY 13, 2009 SYMPOSIA S2-02 DIAGNOSIS: BIOMARKERS S2-02-01
MEASUREMENT OF AMYLOID-BETA PRODUCTION AND CLEARANCE DIRECTLY IN HUMANS
Randall J. Bateman, Washington University, St. Louis, MO, USA. Contact e-mail: [email protected] Background: Production and clearance of central nervous system proteins including amyloid-beta are likely related to Alzheimer’s disease pathophysiology. Techniques to measure this directly in humans has been developed. Methods: Human participants are labeled with a stable isotope amino acid during sampling of blood and cerebrospinal fluid from the CNS. Measurements of labeled and unlabeled CNS proteins over time are made with mass spectrometry. Results: A review of the latest findings of amyloidbeta metabolism and other CNS protein metabolism will be presented. Conclusions: Stable isotope labeling kinetics of CNS proteins in humans are likely to provide practical new information on the pathophysiology of Alzheimer’s disease and the responses to therapeutics which target these proteins.
S2-02-02
THE SWEDISH BRAIN POWER MULTICENTER STUDY: CSF BIOMARKER DATA REPORT
Niklas Mattson, University of Gothenburg, Institute of Neuroscience and Physiology, Go¨teborg, Sweden. Contact e-mail: niklas.mattsson@neuro. gu.se Background: Several studies show that cerebrospinal fluid (CSF) biomarkers have a high diagnostic accuracy for Alzheimer’s disease (AD). Recent studies also show that CSF biomarkers may be useful to identify incipient AD in patients with mild cognitive impairment (MCI), but conclusive large-scale multi-center studies are missing. The objective of this study was to determine the diagnostic accuracy of CSF b-amyloid1-42 (Ab42), total tau protein (T-tau) and tau phosphorylated at position threonine 181 (P-tau) for incipient AD in a large heterogenic group of MCI patients. Methods: The study was designed in accordance with the STARD criteria. Twelve centers in Europe and US participated. Seven hundred fifty subjects with MCI, 529 with AD, and 304 controls were included. MCI subjects were followed for at least two years or until the symptoms had progressed to clinical dementia. Results: During follow-up, 271 MCI patients were diagnosed with AD and 59 with other dementias. MCI patients with incipient AD had lower Ab42 and higher P-tau and T-tau levels than other MCI patients. CSF biomarker levels did not differ between incipient AD patients and AD patients with dementia at baseline. Optimal cut-off levels were defined in the AD with dementia and control groups and tested in the MCI group, where the combination of Ab42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83 % (95% CI 78-88), a specificity of 72 % (95% CI 6876), a positive likelihood ratio of 3.0 (95% CI 2.5-3.4), a negative likelihood ratio of 0.24 (95% CI 0.21-0.28) and an odds ratio of 12.0 (95% CI 7.818.4, p<0.001). Conclusions: This study confirms that CSF Ab42, T-tau and P-tau can identify incipient AD with good accuracy, even in a multicenter setting. These CSF biomarkers may thus be useful as diagnostic tools in memory clinics, and also to enrich clinical MCI trials with incipient AD cases.
S2-02-03
THE ADNI MULTICENTER STUDY: CSF BIOMARKERS DATA REPORT
Leslie M. Shaw, University of Pennsylvania Medical Center, Philadelphia, PA, USA. Contact e-mail: [email protected] Background: The goals of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) biochemical biomarker core include development of standardized biochemical biomarker methods for AD trials and validation of these methods by correlating them with imaging biomarker methods and neuropsychological and behavioral test data from the ADNI cohorts. Methods: Ab1-42, total tau and tau phosphorylated at the threonine 181 position were measured in (a) CSF samples obtained during baseline evaluation of 100 mild AD, 196 mild cognitive impairment (MCI) and 114 elderly cognitively normal (NC) subjects participating in ADNI and in (b) an independent set of 56 autopsy-confirmed AD subjects and 52 age-matched elderly NC using a multicenter-qualified multiplex immunoassay system (Luminex platform and Innogenetics research reagents). Detection of an AD CSF profile for t-tau and Ab1-42 levels in ADNI subjects was achieved using receiver operating characteristic (ROC) cutpoints and logistic regression models derived from the autopsy-confirmed CSF biomarker data. Results: CSF Ab1-42 was the most sensitive biomarker for AD detection in the autopsy-confirmed cohort of pathology-based CSF samples: ROC area under the curve of 0.913 and sensitivity for AD detection (96.4%), negative predictive value (95.2%), specificity for discriminating AD from elderly NC (76.9%), positive predictive value (81.8%) and overall test accuracy of 87%. In the ADNI cohort, a logistic regression model for Ab1-42, t-tau and APOe4 allele count, provided the best assessment delineation of mild AD. An ADlike pathological baseline CSF profile for t-tau/Ab1-42 was detected in 33/ 37 ADNI MCI subjects who converted to probable AD during the first