- Email: [email protected]
Periodontal inflammation effect on cognition depends on the IL-10-1082 gene polymorphism
S320
Poster Presentations P2
Figure. Significance and beta coefficient maps relating plasma levels of BDNF to cortical thickness. P2-038
DETECTION OF TISSUE TRANSGLUTAMINASE WITH NEW ANTIBODIES IN IMMUNOHISTOCHEMISTRY
Carsten J€ ager1, Johannes Wolf2, 1University of Leipzig, Leipzig, Germany; 2 University Hospital Leipzig, Leipzig, Germany. Background: Tissue transglutaminase (tTG) is the most abundantly expressed transglutaminase (TG) enzyme in the human brain. There are some indications for the participation of tTG in the development of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. In brain, tTG is known to be expressed in neurons and astroglia (Wilhelmus et al. 2008). Previous data showed tTG being involved in cross-linking ß-amyloid and tau and therefore contributing to the development of Alzheimer’s disease hallmarks. It has been observed that neurofibrillary tangles and ß-amyloid in senile plaques show immunoreactivity for tTG (Wilhelmus et al. 2008). Furthermore it has been described that transglutaminase activity is increased in Alzheimer’s disease (e.g. Wang et al. 2008). Methods: We tested 12 new monoclonal antibodies with specific reactivity to human tTG (Wolf et al. 2011) on tissue samples of AD brains and age-matched controls. tTG immunoreactivity was compared to tau an amyloid pathology. Additionally we compared our results to those of assays for specific determination of either tTG protein or in-vitro activatable tTG made of adequate regions. Results: The monoclonal antibodies against human tTG showed different immunoreactivity in human brain tissue. Some of them show clear distribution patterns, different in AD brains and controls. Concerning AD pathology we observed a high density of tTG in neurofibrillary tangles and a clear colocalization of tTG and anti-phosphotau antibody. In senile plaques only a light shade of tTG immunoreactivity could be detected with nickel enhanced diaminobenzidine reaction. Some of the antibodies detect tTG associated with reactive Astroglia around senile plaques. Conclusions: Some of the new anti-human tTG antibodies clearly visualize distribution and density of substrate-associated tTG in human brain. The further characterization of their specificity and detected epitopes is just in process. In AD brain, the different density of tTG in aggregated tau and ß-amyloid may be caused due to the different concentrations of lysine in tau and ß-amyloid peptides. Together with the results of quantification of tTG total protein and activity assays, the new antibodies may contribute to further investigation of tTG in human brain and their role in the development of neurodegenerative diseases like AD. P2-039
A MULTIPLEX UPLC-MS/MS-BASED ASSAY FOR AMYLOID b AND RELATED BIOMARKER PEPTIDES IN HUMAN CEREBROSPINAL FLUID
Rand Jenkins1, Omnia Ismaiel2, Shanhua Lin1, Junlong Shao1, Moucun Yuan1, 1PPD, Inc., Richmond, Virginia, United States; 2School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, United States. Background: Aß peptides analysis in CSF has found utility in clinical diagnosis. Aß1-42 CSF levels are known to decrease in AD patients; however,
the population of Aß isoforms is complex, and a “general-purpose” assay that can simultaneously quantify several biomarker peptides is of interest. While specific isoforms like Aß1-42 are typically measured by immunoassays, mass spectrometric techniques are better suited to measure multiple analytes. A solid-phase extraction (SPE)-based UPLCÒ-MS/MS method is described, which provides sensitive analysis of eight biomarker peptides in CSF. In addition to diagnostic Aß markers, Aß1-14 and Aß1-15 are measured as indicators of potential therapeutic g-secretase modulation. Also included is APL1ß28, a nonamyloidogenic Aß-like peptide produced from APLP1 protein by secretases, as a proposed surrogate marker for Aß1-42. Methods: A 200-mL CSF sample is fortified with [15N]-labeled Aß internal standards, 2% BSA, and treated with 200 mL of 5M guanidine HCl at ambient for 60 min. 200 mL of H3PO4 is added and the analytes are isolated using a 96-well Waters Oasis MCX mElution plate. After washing, the analytes are eluted with 50mL of ACN/NH4OH/water (75:10:15 v/v). The extract is analyzed by two-dimensional UPLC, using a Waters XBridge C18 precolumn and ACQUITY BEH300 C18 analytical column, with acetonitrile-high pH reversed-phase gradients. The analytes are trapped on the precolumn, desalted, transferred, separated on the analytical column, and detected by positive electrospray ionization multiple-reaction-monitoring (MRM) using an ABSciex5000 mass spectrometer. Results: The method achieves >50% recovery, and the 2D-UPLC conditions have been optimized for ruggedness and reproducibility. Testing indicates that 4-6-20/25% accuracy and precision can be met for standards and QCs prepared in artificial CSF. Selectivity and standard addition accuracy have been confirmed in human CSF lots. The assay dynamic range extends from 25/50 pg/mL to 10 ng/mL, as appropriate to expected endogenous levels. A fit-for-purpose method validation is being conducted to support study sample analysis. Conclusions: A multiplex SPE-LC-MS/MS method has been developed that provides sensitive targeted detection of multiple Aß and related peptides in CSF in a single assay, which is extremely challenging due to their great hydrophobicity differences and tendency for non-specific binding and self-aggregation.
P2-040
PERIODONTAL INFLAMMATION EFFECT ON COGNITION DEPENDS ON THE IL-10-1082 GENE POLYMORPHISM
Angela Kamer1, K. S. Krabbe2, H. Bruunsgaard2, P. Holm-Pedersen2, E. L. Mortensen2, D. E. Morse1, K. Avlund2, 1NYU College of Dentistry, New York, New York, United States; 2University of Copenhagen, Copenhagen, Denmark. Background: The etiology and pathogenic mechanisms for AD have not been defined, although peripheral inflammation is thought to play a role. Periodontal disease is a prevalent, peripheral infection associated with gram negative, anaerobic bacteria that through localized and systemic inflammatory pathways could contribute to cognitive dysfunction. We hypothesized that subjects with periodontal inflammation (PI) having a genetic profile indicative of a proinflammatory phenotype have lower cognition
Poster Presentations P2 compared to those lacking this genetic profile or subjects without PI. Methods: We analyzed in cross-section 45, 70-year-old Danish subjects with periodontal data as well as data on, cognitive function and single nucleotide polymorphism (SNP) within the Il-10 gene promoter region. Results: The combined effect of periodontal inflammation and IL-10-1082 genotype on Digit Symbol Test (DST) was assessed by analysis of variance that showed a significant interaction between the two independent variables even after adjustments for DST at age 50 and education [F (Interaction) ¼ 3.8, p ¼ 0.03]. This interaction was due to the differential effect of AA/ AG and GG genotype combined with periodontal condition on the cognitive scores: subjects with IL-1082 AA/AG genotype and periodontal inflammation tested lower on the DST (33 6 6.5 and 30 6 8.0) compared to periodontal subjects with IL-1082 GG genotype (41 6 7.9) and subjects without periodontal inflammation (42 6 12). Conclusions: These results are consistent with the literature showing that subjects with IL-10-1082 GG genotype have increased production of the anti-inflammatory cytokine IL-10 compared to subjects with IL-10-1082 AA/AG genotype. These results also support our general hypothesis that periodontal disease may be associated with cognitive dysfunction through its inflammatory component. P2-041
EEG-DERIVED BIOMARKERS OF NORMAL AGERELATED CHANGE IN EPISODIC MEMORY
Kerry Kilborn1, Stephanie Connell1, Zoe Tieges2, Eniko Zsoldos1, 1 Glasgow University, Glasgow, United Kingdom; 2University of Edinburgh, Edinburgh, United Kingdom. Background: In healthy older adults, changes in cognition, including memory, attention, and various executive functions, may be due to normal brain aging. However, not all functions change at equal rates, and some may remain quite robust. This uneven pattern of change contributes to the difficulty in differentiating normal age-related change from pathological deficits, such as those caused by incipient Alzheimer’s disease. In this study, we explore the application of functional biomarkers derived from a non-invasive measure of brain function to characterize change in episodic memory function in healthy older (50 - 85 years) adults. Methods: Participants were healthy volunteers of mid- (50-65 years, mean age 59, N ¼ 50) and older age (67-85 years, mean age79, N ¼ 50). The two groups did not differ on mean MMSE and GDS scores. Subjects performed a computerized, cross-modal "old/new"memory task, while scalp potentials were recorded using 128channel EEG. In the task, paired associates consisting of a simple image and a spoken word were presented simultaneously. Subjects pressed a button on each trial to indicate whether each stimulus pair was previously presented (old) or not (new). Old items were divided into two categories, corresponding to either a short (5 intervening items) or long (39 intervening items) interval from the first (new) presentation. Results: Memory performance (d’ and response latency) of the younger group was significantly better than the older group. There was a significant Memory x Age interaction on the prefrontal P400 amplitude, due to a larger difference between groups on long items. The anterior-central N200 peak latency was significantly shorter for the younger group (178ms) than for older group (188ms). ERPs also revealed memory but not age effects on the anterior N200 amplitude and P600 amplitude. Conclusions: Two cognitive ERP effects – an anterior-central N200, associated with executive function, and a prefrontal P400, associated with episodic encoding, varied as a function of age. In contrast, the N200 and P600 amplitudes were sensitive to memory demands, but did not vary with age. Our findings suggest that ERP measures can differentiate specific age-related changes in episodic and attentional functions from more general memory load effects. P2-043
CORRELATION BETWEEN CSF AMYLOID BETA 1-42 AND PLASMA GLUCOSE/INSULIN IS MODULATED BY APOE4 POLYMORPHISM IN EARLY ONSET SPORADIC ALZHEIMER’S DISEASE (EOAD).
Angela La Sala1, Erika Talassi2, Alessandra Codemo3, Andrea Maria Chiamenti2, Cristina Ruaro2, Donata Gollin4, Anna Peruzzi2, Sarah Poli2, Carlo Gabelli2, 1ULSS9 Ospedale di Treviso, Treviso, Italy;
S321
2 CRIC, Valdagno (VI), Italy; 3ULSS 16 Padova, Padova, Italy; 4Centro Regionale Invecchiamento Cerebrale (Brainaging Regional Center), Valdagno (VI), Italy.
Background: Type2 diabetes (T2D), insulin resistance and presence of apoE4 allele are associated to higher risk of developing Alzheimer’s disease (AD), however little evidence of a possible direct connection between glucose metabolism and amyloid beta 1-42 (Aß)accumulation was found in human. Aim of the present study was to evaluate the possible association between AD CSF biomarkers levels and glucose/insulin metabolism in sporadic EOAD. Methods: 20 sporadic EOAD (NINCDS-ADRDA) consecutive patients, mean age 64.1 6 4.9y, 65% females, MMSE 17.5 6 5.9 were studied. T2D subjects were excluded. CSF levels of A ß 1-42 , total TAU and P-TAU 181 were quantified by ELISA (Innogenetics); apoE genotype was determined by restriction polymorphism analysis. Results: an inverse correlation was found between concentrations of CSF A ß 1-42 and plasmaglucose and insulin levels, and insulin resistance (HOMA-IR), respectively: r ¼ 0.646; p ¼ 0.002; r ¼ 0.462; p ¼ 0.04; r ¼ 0.563; p ¼ 0.01, the correlation with fasting glycaemia was confirmed in two distinct samples. When the patient population was divided by apoE4polymorphism we found that the correlation was present only in theapoE4+ group (r ¼ 0.736, p ¼ 0.01). In addition, CSF total TAU levels were significantly higher in ApoE4 carriers (p ¼ 0.03). Conclusions: Glycaemia and insulin resistance appear to play a direct role in A 1-42 CSF metabolism, at least in this select population of sporadic EOAD patients. When ApoE4 is associated with insulin resistance the patients may be particularly exposed to neurodegeneration as indicated by the higher CSF TAU levels. P2-044
GLYCOGEN SYINTHASE KINASE-3b ACTIVITY IN ELDERLY PATIENTS WITH BIPOLAR DISORDER
Rodolfo Ladeira1, Paula Nunes2, Breno Diniz1, Orestes Forlenza3, 1Faculty of Medicine, University of S~ao Paulo, S~ao Paulo, Brazil; 2Faculty of Medicine - University of S~ao Paulo, S~ao Paulo, Brazil; 3Faculty of Medicine, University of S~ao Paulo, S~ao Paulo - S.P., Brazil. Background: Glycogen synthase kinase-3ß (GSK3ß) is an enzyme present in various biological systems and it is involved in several prevalent diseases, including mood disorders, Alzheimer’s disease, diabetes, and cancer. Bipolar Disorder (BD) has been linked to alterations in GSK3ß. This study aims to evaluate the activity of the enzyme GSK 3ß in elderly patients with bipolar affective disorder compared with healthy elderly. Methods: Platelets were obtained from 18 healthy control subjects and 21 elderly bipolar subjects. The expression of total GSK3ß and phospho-Ser9-GSK3ß in platelets was determined by enzyme immunoassay and also the activity of GSK3ß. The intensity of mood symptoms and the cognitive performance were evaluated by Hamilton Depression Scale 21 items, Young Mania Rating Scale, Cambridge Cognitive Test and the Mini-Mental State Examination. Results: The GSK3ß activity was significantly lower in BD patients than controls. The enzyme activity was not significantly correlated with depressive symptoms, manisc symptoms, or cognitive performance in these elderly patients group. Conclusions: These results suggest that the activity of GSK3B is significantly altered in elderly patients with bipolar disorder, and that this change is not correlated with the severity of depressive symptoms and cognitive deficits. The absence of a group of unmedicated patients did not allow us to say whether this increase in phosphorylated GSK would be related to medication in use or was inherent to the disorder. Further investigations will be needed. P2-045
HIPPOCAMPAL METABOLISM DEFICIT IN ELDERLY WITH MILD COGNITIVE IMPAIRMENT
Anita Lakatos*1, Jerod Rasmussen1, Theo Van Erp1, Frijthof Kruggel1, David Keator1, Steven Potkin1, 1UCI, Irvine, California, United States. Background: Increasing evidence suggests that compromised mitochondrial function contributes to the aging process and may increase the risk of Alzheimer’s disease (AD). Efficient mitochondria as power generators are critical for cellular metabolism and consequently for normal cerebral function. Recent imaging studies demonstrated that decline in cerebral
Poster Presentations P2
Figure. Significance and beta coefficient maps relating plasma levels of BDNF to cortical thickness. P2-038
DETECTION OF TISSUE TRANSGLUTAMINASE WITH NEW ANTIBODIES IN IMMUNOHISTOCHEMISTRY
Carsten J€ ager1, Johannes Wolf2, 1University of Leipzig, Leipzig, Germany; 2 University Hospital Leipzig, Leipzig, Germany. Background: Tissue transglutaminase (tTG) is the most abundantly expressed transglutaminase (TG) enzyme in the human brain. There are some indications for the participation of tTG in the development of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. In brain, tTG is known to be expressed in neurons and astroglia (Wilhelmus et al. 2008). Previous data showed tTG being involved in cross-linking ß-amyloid and tau and therefore contributing to the development of Alzheimer’s disease hallmarks. It has been observed that neurofibrillary tangles and ß-amyloid in senile plaques show immunoreactivity for tTG (Wilhelmus et al. 2008). Furthermore it has been described that transglutaminase activity is increased in Alzheimer’s disease (e.g. Wang et al. 2008). Methods: We tested 12 new monoclonal antibodies with specific reactivity to human tTG (Wolf et al. 2011) on tissue samples of AD brains and age-matched controls. tTG immunoreactivity was compared to tau an amyloid pathology. Additionally we compared our results to those of assays for specific determination of either tTG protein or in-vitro activatable tTG made of adequate regions. Results: The monoclonal antibodies against human tTG showed different immunoreactivity in human brain tissue. Some of them show clear distribution patterns, different in AD brains and controls. Concerning AD pathology we observed a high density of tTG in neurofibrillary tangles and a clear colocalization of tTG and anti-phosphotau antibody. In senile plaques only a light shade of tTG immunoreactivity could be detected with nickel enhanced diaminobenzidine reaction. Some of the antibodies detect tTG associated with reactive Astroglia around senile plaques. Conclusions: Some of the new anti-human tTG antibodies clearly visualize distribution and density of substrate-associated tTG in human brain. The further characterization of their specificity and detected epitopes is just in process. In AD brain, the different density of tTG in aggregated tau and ß-amyloid may be caused due to the different concentrations of lysine in tau and ß-amyloid peptides. Together with the results of quantification of tTG total protein and activity assays, the new antibodies may contribute to further investigation of tTG in human brain and their role in the development of neurodegenerative diseases like AD. P2-039
A MULTIPLEX UPLC-MS/MS-BASED ASSAY FOR AMYLOID b AND RELATED BIOMARKER PEPTIDES IN HUMAN CEREBROSPINAL FLUID
Rand Jenkins1, Omnia Ismaiel2, Shanhua Lin1, Junlong Shao1, Moucun Yuan1, 1PPD, Inc., Richmond, Virginia, United States; 2School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, United States. Background: Aß peptides analysis in CSF has found utility in clinical diagnosis. Aß1-42 CSF levels are known to decrease in AD patients; however,
the population of Aß isoforms is complex, and a “general-purpose” assay that can simultaneously quantify several biomarker peptides is of interest. While specific isoforms like Aß1-42 are typically measured by immunoassays, mass spectrometric techniques are better suited to measure multiple analytes. A solid-phase extraction (SPE)-based UPLCÒ-MS/MS method is described, which provides sensitive analysis of eight biomarker peptides in CSF. In addition to diagnostic Aß markers, Aß1-14 and Aß1-15 are measured as indicators of potential therapeutic g-secretase modulation. Also included is APL1ß28, a nonamyloidogenic Aß-like peptide produced from APLP1 protein by secretases, as a proposed surrogate marker for Aß1-42. Methods: A 200-mL CSF sample is fortified with [15N]-labeled Aß internal standards, 2% BSA, and treated with 200 mL of 5M guanidine HCl at ambient for 60 min. 200 mL of H3PO4 is added and the analytes are isolated using a 96-well Waters Oasis MCX mElution plate. After washing, the analytes are eluted with 50mL of ACN/NH4OH/water (75:10:15 v/v). The extract is analyzed by two-dimensional UPLC, using a Waters XBridge C18 precolumn and ACQUITY BEH300 C18 analytical column, with acetonitrile-high pH reversed-phase gradients. The analytes are trapped on the precolumn, desalted, transferred, separated on the analytical column, and detected by positive electrospray ionization multiple-reaction-monitoring (MRM) using an ABSciex5000 mass spectrometer. Results: The method achieves >50% recovery, and the 2D-UPLC conditions have been optimized for ruggedness and reproducibility. Testing indicates that 4-6-20/25% accuracy and precision can be met for standards and QCs prepared in artificial CSF. Selectivity and standard addition accuracy have been confirmed in human CSF lots. The assay dynamic range extends from 25/50 pg/mL to 10 ng/mL, as appropriate to expected endogenous levels. A fit-for-purpose method validation is being conducted to support study sample analysis. Conclusions: A multiplex SPE-LC-MS/MS method has been developed that provides sensitive targeted detection of multiple Aß and related peptides in CSF in a single assay, which is extremely challenging due to their great hydrophobicity differences and tendency for non-specific binding and self-aggregation.
P2-040
PERIODONTAL INFLAMMATION EFFECT ON COGNITION DEPENDS ON THE IL-10-1082 GENE POLYMORPHISM
Angela Kamer1, K. S. Krabbe2, H. Bruunsgaard2, P. Holm-Pedersen2, E. L. Mortensen2, D. E. Morse1, K. Avlund2, 1NYU College of Dentistry, New York, New York, United States; 2University of Copenhagen, Copenhagen, Denmark. Background: The etiology and pathogenic mechanisms for AD have not been defined, although peripheral inflammation is thought to play a role. Periodontal disease is a prevalent, peripheral infection associated with gram negative, anaerobic bacteria that through localized and systemic inflammatory pathways could contribute to cognitive dysfunction. We hypothesized that subjects with periodontal inflammation (PI) having a genetic profile indicative of a proinflammatory phenotype have lower cognition
Poster Presentations P2 compared to those lacking this genetic profile or subjects without PI. Methods: We analyzed in cross-section 45, 70-year-old Danish subjects with periodontal data as well as data on, cognitive function and single nucleotide polymorphism (SNP) within the Il-10 gene promoter region. Results: The combined effect of periodontal inflammation and IL-10-1082 genotype on Digit Symbol Test (DST) was assessed by analysis of variance that showed a significant interaction between the two independent variables even after adjustments for DST at age 50 and education [F (Interaction) ¼ 3.8, p ¼ 0.03]. This interaction was due to the differential effect of AA/ AG and GG genotype combined with periodontal condition on the cognitive scores: subjects with IL-1082 AA/AG genotype and periodontal inflammation tested lower on the DST (33 6 6.5 and 30 6 8.0) compared to periodontal subjects with IL-1082 GG genotype (41 6 7.9) and subjects without periodontal inflammation (42 6 12). Conclusions: These results are consistent with the literature showing that subjects with IL-10-1082 GG genotype have increased production of the anti-inflammatory cytokine IL-10 compared to subjects with IL-10-1082 AA/AG genotype. These results also support our general hypothesis that periodontal disease may be associated with cognitive dysfunction through its inflammatory component. P2-041
EEG-DERIVED BIOMARKERS OF NORMAL AGERELATED CHANGE IN EPISODIC MEMORY
Kerry Kilborn1, Stephanie Connell1, Zoe Tieges2, Eniko Zsoldos1, 1 Glasgow University, Glasgow, United Kingdom; 2University of Edinburgh, Edinburgh, United Kingdom. Background: In healthy older adults, changes in cognition, including memory, attention, and various executive functions, may be due to normal brain aging. However, not all functions change at equal rates, and some may remain quite robust. This uneven pattern of change contributes to the difficulty in differentiating normal age-related change from pathological deficits, such as those caused by incipient Alzheimer’s disease. In this study, we explore the application of functional biomarkers derived from a non-invasive measure of brain function to characterize change in episodic memory function in healthy older (50 - 85 years) adults. Methods: Participants were healthy volunteers of mid- (50-65 years, mean age 59, N ¼ 50) and older age (67-85 years, mean age79, N ¼ 50). The two groups did not differ on mean MMSE and GDS scores. Subjects performed a computerized, cross-modal "old/new"memory task, while scalp potentials were recorded using 128channel EEG. In the task, paired associates consisting of a simple image and a spoken word were presented simultaneously. Subjects pressed a button on each trial to indicate whether each stimulus pair was previously presented (old) or not (new). Old items were divided into two categories, corresponding to either a short (5 intervening items) or long (39 intervening items) interval from the first (new) presentation. Results: Memory performance (d’ and response latency) of the younger group was significantly better than the older group. There was a significant Memory x Age interaction on the prefrontal P400 amplitude, due to a larger difference between groups on long items. The anterior-central N200 peak latency was significantly shorter for the younger group (178ms) than for older group (188ms). ERPs also revealed memory but not age effects on the anterior N200 amplitude and P600 amplitude. Conclusions: Two cognitive ERP effects – an anterior-central N200, associated with executive function, and a prefrontal P400, associated with episodic encoding, varied as a function of age. In contrast, the N200 and P600 amplitudes were sensitive to memory demands, but did not vary with age. Our findings suggest that ERP measures can differentiate specific age-related changes in episodic and attentional functions from more general memory load effects. P2-043
CORRELATION BETWEEN CSF AMYLOID BETA 1-42 AND PLASMA GLUCOSE/INSULIN IS MODULATED BY APOE4 POLYMORPHISM IN EARLY ONSET SPORADIC ALZHEIMER’S DISEASE (EOAD).
Angela La Sala1, Erika Talassi2, Alessandra Codemo3, Andrea Maria Chiamenti2, Cristina Ruaro2, Donata Gollin4, Anna Peruzzi2, Sarah Poli2, Carlo Gabelli2, 1ULSS9 Ospedale di Treviso, Treviso, Italy;
S321
2 CRIC, Valdagno (VI), Italy; 3ULSS 16 Padova, Padova, Italy; 4Centro Regionale Invecchiamento Cerebrale (Brainaging Regional Center), Valdagno (VI), Italy.
Background: Type2 diabetes (T2D), insulin resistance and presence of apoE4 allele are associated to higher risk of developing Alzheimer’s disease (AD), however little evidence of a possible direct connection between glucose metabolism and amyloid beta 1-42 (Aß)accumulation was found in human. Aim of the present study was to evaluate the possible association between AD CSF biomarkers levels and glucose/insulin metabolism in sporadic EOAD. Methods: 20 sporadic EOAD (NINCDS-ADRDA) consecutive patients, mean age 64.1 6 4.9y, 65% females, MMSE 17.5 6 5.9 were studied. T2D subjects were excluded. CSF levels of A ß 1-42 , total TAU and P-TAU 181 were quantified by ELISA (Innogenetics); apoE genotype was determined by restriction polymorphism analysis. Results: an inverse correlation was found between concentrations of CSF A ß 1-42 and plasmaglucose and insulin levels, and insulin resistance (HOMA-IR), respectively: r ¼ 0.646; p ¼ 0.002; r ¼ 0.462; p ¼ 0.04; r ¼ 0.563; p ¼ 0.01, the correlation with fasting glycaemia was confirmed in two distinct samples. When the patient population was divided by apoE4polymorphism we found that the correlation was present only in theapoE4+ group (r ¼ 0.736, p ¼ 0.01). In addition, CSF total TAU levels were significantly higher in ApoE4 carriers (p ¼ 0.03). Conclusions: Glycaemia and insulin resistance appear to play a direct role in A 1-42 CSF metabolism, at least in this select population of sporadic EOAD patients. When ApoE4 is associated with insulin resistance the patients may be particularly exposed to neurodegeneration as indicated by the higher CSF TAU levels. P2-044
GLYCOGEN SYINTHASE KINASE-3b ACTIVITY IN ELDERLY PATIENTS WITH BIPOLAR DISORDER
Rodolfo Ladeira1, Paula Nunes2, Breno Diniz1, Orestes Forlenza3, 1Faculty of Medicine, University of S~ao Paulo, S~ao Paulo, Brazil; 2Faculty of Medicine - University of S~ao Paulo, S~ao Paulo, Brazil; 3Faculty of Medicine, University of S~ao Paulo, S~ao Paulo - S.P., Brazil. Background: Glycogen synthase kinase-3ß (GSK3ß) is an enzyme present in various biological systems and it is involved in several prevalent diseases, including mood disorders, Alzheimer’s disease, diabetes, and cancer. Bipolar Disorder (BD) has been linked to alterations in GSK3ß. This study aims to evaluate the activity of the enzyme GSK 3ß in elderly patients with bipolar affective disorder compared with healthy elderly. Methods: Platelets were obtained from 18 healthy control subjects and 21 elderly bipolar subjects. The expression of total GSK3ß and phospho-Ser9-GSK3ß in platelets was determined by enzyme immunoassay and also the activity of GSK3ß. The intensity of mood symptoms and the cognitive performance were evaluated by Hamilton Depression Scale 21 items, Young Mania Rating Scale, Cambridge Cognitive Test and the Mini-Mental State Examination. Results: The GSK3ß activity was significantly lower in BD patients than controls. The enzyme activity was not significantly correlated with depressive symptoms, manisc symptoms, or cognitive performance in these elderly patients group. Conclusions: These results suggest that the activity of GSK3B is significantly altered in elderly patients with bipolar disorder, and that this change is not correlated with the severity of depressive symptoms and cognitive deficits. The absence of a group of unmedicated patients did not allow us to say whether this increase in phosphorylated GSK would be related to medication in use or was inherent to the disorder. Further investigations will be needed. P2-045
HIPPOCAMPAL METABOLISM DEFICIT IN ELDERLY WITH MILD COGNITIVE IMPAIRMENT
Anita Lakatos*1, Jerod Rasmussen1, Theo Van Erp1, Frijthof Kruggel1, David Keator1, Steven Potkin1, 1UCI, Irvine, California, United States. Background: Increasing evidence suggests that compromised mitochondrial function contributes to the aging process and may increase the risk of Alzheimer’s disease (AD). Efficient mitochondria as power generators are critical for cellular metabolism and consequently for normal cerebral function. Recent imaging studies demonstrated that decline in cerebral