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O2-02-07 Can CSF P-TAU differentiate MCI cases with incipient Alzeheimer disease from stable MCI cases?
Oral Session 02-02: Diagnosis & Clinical Course - Biomarkers 1 certain markers in cerebrospinal fluid (CSF). Methods: Here we applied a proteomic approach (surface enhanced laser desorption/ionization timeof-flight mass spectrometry) to characterize the CSF of 16 patients with sporadic CJD, 16 with other dementias (OD) and 16 without dementia (NDC). These findings were compared to standard biomarkers (e.g. tau protein and 14-3-3 proteins) Results: We identified 103 peaks in the range between 3.8 and 20 kDa The intensities of 48 peaks were demonstrated to be significantly different. We were able to achieve a cut-off point for the intensities of the peak at 8.6 kDa at which CJD and OD could be differentiated with 100% specificity and 94% sensitivity. In our study we showed that the analysis of just one peak achieved a slightly better diagnostic sensitivity and specificity compared with the analysis of tau protein and 14-3-3 proteins. We also show that combinatory analysis of these peaks will achieve even better results in the differential diagnosis of dementias. Contusion: This proteomic approach seem to be a valuable tool in the differential diagnosis of dementias.
0 2 - 0 2 - 0 6 i INSULIN EFFECTS ON PLASMA BETA-AMYLOID L E V E L S IN N O R M A L ADULTS AND PATIENTS WITH AD Suzanne Craft* 1, Jake Kulstad 1, Pattie Green 1, David Cook 1, G. Stennis Watson I, Laura D. Baker 1, Mark Reger 1, Brenna Cholerton 1, Sanjay Asthana 2, Steven Plymate 1.1 University of Washington/VA Puget
Sound, Seattle, WA, USA; 2University of Wisconsin, Madison, WI, USA. Contact e-mail: scrafl@ u.washington.edu Background: Insulin modulates levels of the beta amyloid (A13) protein in vitro and in an age-dependent manner in the CSF of older humans. In in vitro studies, insulin promotes release of A1340 and A1342 and inhibits their degradation. Older humans show increased CSF A1342 in response to acute elevations in insulin. No study to date has examined insulin effects on plasma amyloid levels, which may have relevance to Alzheimer's disease (AD) pathogenesis, given suggestions that A13 is transported between brain and periphery. Objective: We determined the effects of raising insulin on plasma levels of A1340 and A1342 in healthy older adults and in persons with AD. Methods: Forty-four fasting patients with AD and 46 controls each completed two infusions on separate days in counterbalanced order, receiving either a saline infusion, or an infusion of 1.0 mU.kg.min insulin with variable dextrose to maintain euglycemia. The latter infusion produced moderately high physiologic insulin levels of ~ 80 tzU/ml. Plasma was sampled after 90 minutes of infusion. Plasma A1340 and 42 were measured by sandwich ELISA, and subjected to repeated measures ANOVA with age and body mass index (BMI) as covariates. Results: For normal adults, plasma A1340 increased following insulin infusion with greater increases for younger adults (p = 0.03). For adults with AD, insulin induced changes in plasma A1340 were associated with greater BMI (p = 0.05). Increases in plasma A1342 levels were inversely related to A1340 changes for AD patients, and were predicted in a stepwise regression model by A1340 changes (p = 0.01) and BMI (p = 0.06). Conclusions: Our results demonstrate that insulin modulates plasma A[3 40 levels in an age-dependent manner for normal adults. Larger BMI, a recently identified risk factor for AD, was associated with higher A1342 levels in response to insulin. For AD patients, the inverse relationship between plasma A1340 and 42 changes in response to insulin may be due in part to a processing shift that favors production of the longer, more pathogenetic species of A13. Future studies will examine whether the pattern of reduced plasma A1340 and increased plasma A1342 in response to insulin is a potential biomarker of AD vulnerability.
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0 2 - 0 2 - 0 7 | CAN CSF P-TAU DIFFERENTIATE MCI CASES WITH INCIPIENT ALZHEIMER DISEASE FROM STABLE MCI CASES? Niels Andreasen .1 , Buerger Katarina 2, Hugo Vanderstichele3 , Eugeen Vandermechelen 3, Haratd Hampel 4, Kaj Blennow 5.1Neurotec '
Stockholm, Sweden; eDept of Psychiatry, Ludwig-Maximilian University, Munic, Germany; 3Innogenetics, Ghent, Belgium; 4Dept of Psychiatry, Ludwig-Maximilian University, Munic, Germany; 5Dept of Clinical Neuroscience, University of GOteborg, Sweden. Contact e-mail: niels.andreasen @neurotec.ki.se Background: Current therapeutic compounds for treatment of Alzheimer disease (AD) e.g. acetylchoLineesterase inhibitors and NMDA-receptor inhibitors demand an improvement of the diagnostic accuracy. With future compounds such as vaccination regimes, 13- and y-secretase inhibitors and 13-sheet breakers the need for a very early and reliable diagnosis of AD and even incipient AD is pressing, as one might expect the greatest potential in the early phase of the disease. One tool to attain this is the development of reliable biomarkers in the cerebrospinal fluid (CSF). Phosphorylated tau (PHF-tau) is the main component of neurofibrillary tangles, which is one of the defining lesions in AD brains. PHF-tau is secreted to body fluids including plasma and cerebrospinal fluid (CSF). Objective(s): To examine the diagnostic sensitivity of CSF PHF-tau(181). Methods: A communitybased sample of consecutive MCI patients with two years follow up. Results: CSF-samples of 66 AD patients (76.5 4- 7,8 years), 15 MCI patients deteriorating to AD (76.9± 6.2 years), 26 MCI (63.3 4- 12.5 years) patients remaining stable and 29 healthy controls (67.3 4- 5.1 years). CSF PHF-tau was increased (p < 0.001) in AD (99.64- 41.2 pg/mL), in MCI deteriorating to AD (95.54- 29.5 pg/mL) as compared with those MCI patients who remained stable (44.24- 17.7 pg/mL) and healthy controls (56.7± 23.3 pg/mL). Conclusions: Thus, the sensitivity of CSF PHF-tau as a diagnostic marker for MCI patients, who will deteriorate into AD is high. These findings suggest that high CSF PHF-tau in MCI patients may predict an deterioration into AD and that they are actually preclinical or incipient AD cases and should be treated. On the other hand in MCI patients with normal CSF PHF-tau one should only have a follow-up. In the evaluation of patients with MCI, lumbar puncture is a harmless procedure, with minimal risk for complications, such as headache (Andreasen et al, Arch Neuro12001 ;58:3739). This suggest that this analysis may be of great value in discrimination of the MCI patients that will deteriorate into AD and thus are in need of treatment when drags may have the greatest potential of being effective.
IO2-02-08 ] LEVELS OF AUTOANTIBODIES TO REDOX-MODIFIED ABETA ARE ATTENUATED IN THE PLASMA OF ALZHEIMER'S DISEASE PATIENTS Robert D. Moir* t, Katya A. Tseitlln 1, Stephanie Soscia 1, Bradley T. Hyman 2, Michael C. Irizarry 2, Rudolph E. Tanzi 1.1Genetics andAging
Research Unit, Massachusetts General Hospital, Charlestown, MA, USA; 2Neurology, Massachusetts General Hospital, Charlestown, MA, USA. Contact e-mail: moir @helix.mgh, harvard, edu Accumulation of the Abeta protein as beta-amyloid deposits is the pathological hallmark of Alzheimer's disease (AD). Interest in autoimmunity to Abeta has been stimulated by recent findings that amyloid burden in transgenic animal models can be attenuated by circulating anti-Abeta antibodies. The presence of anti-Abeta immunoreactivity in human serum and CSF was first reported over a decade ago. However, a consensus has yet to emerged as to whether anti-Abeta autoantibodies are elevated, depressed, or unchanged in AD patients as compared to non-demented controls. To date, experiments have used synthetic unmodified monomeric Abeta peptides to test for autoimmunity. However, analysis of material purified from human tissue suggest that up to 40% of the Abeta pool in AD brain exists as cross-linked dimeric and low molecular weight oligomeric species. Recent studies also suggest that cross-finked low molecular weight Abeta oligomers maybe the primary neurotoxic agent in AD. We will present evidence for autoimmunity to soluble, low molecular weight, redox cross-linked oligomeric
0 2 - 0 2 - 0 6 i INSULIN EFFECTS ON PLASMA BETA-AMYLOID L E V E L S IN N O R M A L ADULTS AND PATIENTS WITH AD Suzanne Craft* 1, Jake Kulstad 1, Pattie Green 1, David Cook 1, G. Stennis Watson I, Laura D. Baker 1, Mark Reger 1, Brenna Cholerton 1, Sanjay Asthana 2, Steven Plymate 1.1 University of Washington/VA Puget
Sound, Seattle, WA, USA; 2University of Wisconsin, Madison, WI, USA. Contact e-mail: scrafl@ u.washington.edu Background: Insulin modulates levels of the beta amyloid (A13) protein in vitro and in an age-dependent manner in the CSF of older humans. In in vitro studies, insulin promotes release of A1340 and A1342 and inhibits their degradation. Older humans show increased CSF A1342 in response to acute elevations in insulin. No study to date has examined insulin effects on plasma amyloid levels, which may have relevance to Alzheimer's disease (AD) pathogenesis, given suggestions that A13 is transported between brain and periphery. Objective: We determined the effects of raising insulin on plasma levels of A1340 and A1342 in healthy older adults and in persons with AD. Methods: Forty-four fasting patients with AD and 46 controls each completed two infusions on separate days in counterbalanced order, receiving either a saline infusion, or an infusion of 1.0 mU.kg.min insulin with variable dextrose to maintain euglycemia. The latter infusion produced moderately high physiologic insulin levels of ~ 80 tzU/ml. Plasma was sampled after 90 minutes of infusion. Plasma A1340 and 42 were measured by sandwich ELISA, and subjected to repeated measures ANOVA with age and body mass index (BMI) as covariates. Results: For normal adults, plasma A1340 increased following insulin infusion with greater increases for younger adults (p = 0.03). For adults with AD, insulin induced changes in plasma A1340 were associated with greater BMI (p = 0.05). Increases in plasma A1342 levels were inversely related to A1340 changes for AD patients, and were predicted in a stepwise regression model by A1340 changes (p = 0.01) and BMI (p = 0.06). Conclusions: Our results demonstrate that insulin modulates plasma A[3 40 levels in an age-dependent manner for normal adults. Larger BMI, a recently identified risk factor for AD, was associated with higher A1342 levels in response to insulin. For AD patients, the inverse relationship between plasma A1340 and 42 changes in response to insulin may be due in part to a processing shift that favors production of the longer, more pathogenetic species of A13. Future studies will examine whether the pattern of reduced plasma A1340 and increased plasma A1342 in response to insulin is a potential biomarker of AD vulnerability.
$35
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0 2 - 0 2 - 0 7 | CAN CSF P-TAU DIFFERENTIATE MCI CASES WITH INCIPIENT ALZHEIMER DISEASE FROM STABLE MCI CASES? Niels Andreasen .1 , Buerger Katarina 2, Hugo Vanderstichele3 , Eugeen Vandermechelen 3, Haratd Hampel 4, Kaj Blennow 5.1Neurotec '
Stockholm, Sweden; eDept of Psychiatry, Ludwig-Maximilian University, Munic, Germany; 3Innogenetics, Ghent, Belgium; 4Dept of Psychiatry, Ludwig-Maximilian University, Munic, Germany; 5Dept of Clinical Neuroscience, University of GOteborg, Sweden. Contact e-mail: niels.andreasen @neurotec.ki.se Background: Current therapeutic compounds for treatment of Alzheimer disease (AD) e.g. acetylchoLineesterase inhibitors and NMDA-receptor inhibitors demand an improvement of the diagnostic accuracy. With future compounds such as vaccination regimes, 13- and y-secretase inhibitors and 13-sheet breakers the need for a very early and reliable diagnosis of AD and even incipient AD is pressing, as one might expect the greatest potential in the early phase of the disease. One tool to attain this is the development of reliable biomarkers in the cerebrospinal fluid (CSF). Phosphorylated tau (PHF-tau) is the main component of neurofibrillary tangles, which is one of the defining lesions in AD brains. PHF-tau is secreted to body fluids including plasma and cerebrospinal fluid (CSF). Objective(s): To examine the diagnostic sensitivity of CSF PHF-tau(181). Methods: A communitybased sample of consecutive MCI patients with two years follow up. Results: CSF-samples of 66 AD patients (76.5 4- 7,8 years), 15 MCI patients deteriorating to AD (76.9± 6.2 years), 26 MCI (63.3 4- 12.5 years) patients remaining stable and 29 healthy controls (67.3 4- 5.1 years). CSF PHF-tau was increased (p < 0.001) in AD (99.64- 41.2 pg/mL), in MCI deteriorating to AD (95.54- 29.5 pg/mL) as compared with those MCI patients who remained stable (44.24- 17.7 pg/mL) and healthy controls (56.7± 23.3 pg/mL). Conclusions: Thus, the sensitivity of CSF PHF-tau as a diagnostic marker for MCI patients, who will deteriorate into AD is high. These findings suggest that high CSF PHF-tau in MCI patients may predict an deterioration into AD and that they are actually preclinical or incipient AD cases and should be treated. On the other hand in MCI patients with normal CSF PHF-tau one should only have a follow-up. In the evaluation of patients with MCI, lumbar puncture is a harmless procedure, with minimal risk for complications, such as headache (Andreasen et al, Arch Neuro12001 ;58:3739). This suggest that this analysis may be of great value in discrimination of the MCI patients that will deteriorate into AD and thus are in need of treatment when drags may have the greatest potential of being effective.
IO2-02-08 ] LEVELS OF AUTOANTIBODIES TO REDOX-MODIFIED ABETA ARE ATTENUATED IN THE PLASMA OF ALZHEIMER'S DISEASE PATIENTS Robert D. Moir* t, Katya A. Tseitlln 1, Stephanie Soscia 1, Bradley T. Hyman 2, Michael C. Irizarry 2, Rudolph E. Tanzi 1.1Genetics andAging
Research Unit, Massachusetts General Hospital, Charlestown, MA, USA; 2Neurology, Massachusetts General Hospital, Charlestown, MA, USA. Contact e-mail: moir @helix.mgh, harvard, edu Accumulation of the Abeta protein as beta-amyloid deposits is the pathological hallmark of Alzheimer's disease (AD). Interest in autoimmunity to Abeta has been stimulated by recent findings that amyloid burden in transgenic animal models can be attenuated by circulating anti-Abeta antibodies. The presence of anti-Abeta immunoreactivity in human serum and CSF was first reported over a decade ago. However, a consensus has yet to emerged as to whether anti-Abeta autoantibodies are elevated, depressed, or unchanged in AD patients as compared to non-demented controls. To date, experiments have used synthetic unmodified monomeric Abeta peptides to test for autoimmunity. However, analysis of material purified from human tissue suggest that up to 40% of the Abeta pool in AD brain exists as cross-linked dimeric and low molecular weight oligomeric species. Recent studies also suggest that cross-finked low molecular weight Abeta oligomers maybe the primary neurotoxic agent in AD. We will present evidence for autoimmunity to soluble, low molecular weight, redox cross-linked oligomeric