- Email: [email protected]
P3-039 Simultaneous measurement of Aβ(1–42), tau, phosphorylated tau in cerebrospinal fluid using the xmap™ technology
Poster Session P3: Diagnosis and Disease Progression - CSF Markers
$362
~ C S F
DOPAC L E V E L S P R E D I C T A G G R E S S I V E AND AGITATED BEHAVIOR IN FTD PATIENTS
Sebastiaan Engelborghs* 1,2, Karen Maertens 1, Ellen Vloeberghs 1, Peter Mari~n 2, Anoek Symons 2, Veerle Ketels 2, Nore Somers 2, Guy Nagels 1, Bartold Marescau 1, Peter Paul De Deyn 1,2.1 University of Antwerp, Antwerp, Belgium; 2Middelheim General Hospital, Antwerp, Belgium. Contact e.mail: [email protected]
Objective(s): A prospective, longitudinal study on neurochemicai correlates of cognition and behavioral and psychological signs and symptoms of dementia (BPSD) was set up, performing baseline lumbar punctures (LP) and behavioral assessments in dementia patients. CSF levels of dopamine and serotonin metabolites were determined simultaneously to study interactions between both neurotransmitter systems. Methods: Patients with probable Alzheimer's disease (AD) (N = 177), mixed dementia (N = 32), frontotemporal dementia (FFD) (N = 27) and dementia with Lewy bodies (DLB) (N = 20) were included. At baseline, a neuropsychological examination was performed and behavior was assessed using behavioral assessment scales: Middelheim Frontality Score (MFS), Behave-AD, Cohen-Mansfield Agitation Inventory (CMAI) and Cornell Scale for Depression in Dementia. CSF DOPAC, 5HIAA and HVA levels were determined by HPLC and ECD. Results: Covariability in CSF 5HIAA and HVA levels was observed in the total population (GDS: R = 0.470; P < 0.0001). The CSF HVA/5HIAA ratio correlated negatively with dementia severity in AD (R= -0.188; P = 0.019) and F r D patients (MMSE: R = 0.551; P = 0.004). Aggressive behavior correlated negatively (R= -0.168; P = 0.030) and apathy positively (R = 0.165; P = 0.035) with CSF 5HIAA levels in AD patients. High CSF DOPAC levels were associated with agitation and aggression in F r D patients (R = 0.533; P = 0,005) and predicted future aggressive and agitated behavior (CSF DOPAC levels > 0.5 ng/ml predicted having a CMAI total score of >40 one year later with a PPV = 1.0). The CSF HVA/5HIAA ratio correlated with aggressive behavior in FTD patients. In DLB patients, apathy (R= -0.522; P = 0.026) and the MFS score (R= -0.566; P = 0.014) correlated negatively with CSF DOPAC levels. Conclusions: The CSF HVA/5HIAA ratio reflecting tonic serotonergic modulation of dopaminergic activity, was negatively associated with dementia severity in AD and FTD patients, pointing to a non-disease specific effect of the serotonergic neurotransmitter system on cognition. This study demonstrated that the nenrochemical substrates of BPSD are disease-specific: (1) high CSF DOPAC levels were associated with agitation and aggression in FTD patients and predicted future aggressive and agitated behavior; (2) low CSF DOPAC levels were associated with increased frontal lobe symptoms like apathy in DLB patients; (3) in AD, apathy might be related to changed serotonergic activity, possibly exerting its effects through altered modulation of the dopaminergic neurotransmitter system.
~ H I G H
PLASMA INSULIN LEVELS PROVOKE INCREASES IN C E N T R A L BUT NOT P E R I P H E R A L CYTOKINE LEVELS: R E L A T I O N S H I P TO CSF AND PLASMA BETA A M Y L O I D
Mark Fishel* 1, Thomas Montine 2, Qin Wang 2, Pattie Green 2, Jake Knistad 1, G. Stennis Watson 1, Elaine Peskind I , Laura D. Baker 1, Sanjay Asthana 3, Stephen Plymate ~, David Cook 1, Suzanne Craft 1. 1University of Washington/VAPSHCS, Seattle, WA, USA; 2 University of Washington, Seattle, WA, USA; 3 University of Wisconsin, Madison, WI, USA. Contact e-mail: [email protected]
Background: In vitro and animal studies suggest that inflammation interacts with processing and deposition of A[~, a key protein linked to AD pathology. In the periphery, insulin modulates many aspects of the inflammatory network. Insulin also modulates A[~ levels by promoting its release from intracellular neuronal compartments and by inhibiting its degradation by the metalloprotease insulin degrading enzyme (IDE). Hyperinsulinemia and insulin resistance have been identified as risk factors for AD, raising the possibility that insulin-mediated effects on inflammation may contribute to this increased risk. In the present study, we examined the effects of raising peripheral insulin to levels associated with insulin resistant conditions
such as T2DM on plasma and cerebrospinal fluid (CSF) inflammatory markers and beta amyloid in 15 healthy older adults mad 7 patients with mild AD. Methods: Fasting participants received two IV infusions on separate mornings, consisting of saline, or 1 mU.kg -1 .min -1 insulin with variable dextrose to maintain fasting glucose levels. Following 90 minutes of infusion, plasma and CSF were collected. Results: Insulin increased CSF F2-isoprostane and cytokines (p < 0.01). Furthermore, insulin induced changes in plasma and CSF concentrations of both short and long species of beta amyloid (AIM0, A[~2, p < 0.05), and these changes were significantly correlated with increased F2-isoprostane and cytokine levels, as well as with CSF apolipoprotein E levels. Interestingly, no changes were observed in plasma cytokine levels. Conclusions: These resuks suggest that hyperinsulinemia associated with disorders such as T2DM provokes synchronous elevations in inflammatory markers and A[342 in the brain, thereby potentially increasing the risk of AD.
~P-3f~
SIMULTANEOUS M E A S U R E M E N T OF A[~(1-42),TAU,
PHOSPHORYLATED TAU IN CEREBROSPINAL FLUID USING T H E X M A P TM T E C H N O L O G Y Annika Olsson*. Institute of Clinical Neuroscience, Mtlndal, Sweden. Contact e-mail: [email protected]
Background: Alzheimer's disease (AD) is neurnpathologicaily characterized by abnormal accumulations of intracellular neurofibrillary tangles, extracellular amyloid plaques and neuronal degeneration. Neurofibrillary tangles and amyloid plaques are mainly composed of abnormally hyperphosphorylated tau protein (P-TAU) and the 42 amino acid long [~-amyloid peptide (A$(142)), respectively. Due to the heterogeneous aetiology of AD, a set of several biomarkers is probably required for an accurate diagnosis and discrimination from other neurological diseases. At present, quantification of A~(1-42), tan and P-TAU in cerebrospinal fluid (CSF) has shown to be useful for clinical diagnosis of AD. The microsphere-based xMAPTM technology (Luminex, Austin, Texas, US) is a multiparameter flow cytometer technique that makes it possible to simultaneously analyze several biomarkers in a single CSF sample. Objective(s): The purpose of this study was to evaluate a multipararneter microsphere-based assay for simultaneous quantification of A~(1-42), tan and P-TAU181p (a research version of the 1NNO-BIA AlzBio3, Innogenetics N.V., Gent) in CSE Methods: The xMAFT M technology was compared with ELISA methods for the same analytes. The diagnostic potentials of these molecular markers for AD were evaluated by analyzing CSF samples for A[~(1-42),tan, and P-TAU(lslP) from in 78 AD patients, 15 patient with MCI with progression to AD (MCI-AD), 53 healthy controls and 128 patients with other neurological diagnoses. Results: We showed that the xMAP TM technology provide high reproducibility and results in a diagnostic sensitivity for AD and specifcity to distinguish AD from other neurological disorders that are in the same range as for ELISA methods Conclusions: The microsphere-based xMAP TM technology provides other biological markers to be added to the xMAP TM CSF panel, which in the future might give new better tools for the clinical diagnosis of AD and other neurodegenerative disorders.
~
D E V E L O P M E N T AND VALIDATION O F HUMAN
A[342 ASSAY WITH SPECIFIC MEASUREMENT OF H U M A N A~1-42 IN NATURAL SAMPLES Jimin Wang*, Vimai Patel, Chun Ran, Lynda Zorn, Kevin Reagan. BioSource, Camarillo, CA, USA. Contact e-mail: [email protected] Alzheimer's Disease (AD) is characterized by the presence of redundant senile plaques. The major protein component of these plaques is O-amyloid peptide (A[~), a 40 to 43 amino acid peptide cleaved from amyloid precursor protein by [~-secretase (e.g., BACE) and a putative y secretase. Increased release of the 'longer forms' of A[~ peptide, A~42 or ARM3, which have a greater tendency to aggregate than AIM0, occurs in individuals expressing certain genetic mutations, expressing certain ApoE alleles, or may involve other, still undiscovered, factors. Some researchers theorize that it is this increased release of A~42/A[~43 which leads to the abnormal deposition of
$362
~ C S F
DOPAC L E V E L S P R E D I C T A G G R E S S I V E AND AGITATED BEHAVIOR IN FTD PATIENTS
Sebastiaan Engelborghs* 1,2, Karen Maertens 1, Ellen Vloeberghs 1, Peter Mari~n 2, Anoek Symons 2, Veerle Ketels 2, Nore Somers 2, Guy Nagels 1, Bartold Marescau 1, Peter Paul De Deyn 1,2.1 University of Antwerp, Antwerp, Belgium; 2Middelheim General Hospital, Antwerp, Belgium. Contact e.mail: [email protected]
Objective(s): A prospective, longitudinal study on neurochemicai correlates of cognition and behavioral and psychological signs and symptoms of dementia (BPSD) was set up, performing baseline lumbar punctures (LP) and behavioral assessments in dementia patients. CSF levels of dopamine and serotonin metabolites were determined simultaneously to study interactions between both neurotransmitter systems. Methods: Patients with probable Alzheimer's disease (AD) (N = 177), mixed dementia (N = 32), frontotemporal dementia (FFD) (N = 27) and dementia with Lewy bodies (DLB) (N = 20) were included. At baseline, a neuropsychological examination was performed and behavior was assessed using behavioral assessment scales: Middelheim Frontality Score (MFS), Behave-AD, Cohen-Mansfield Agitation Inventory (CMAI) and Cornell Scale for Depression in Dementia. CSF DOPAC, 5HIAA and HVA levels were determined by HPLC and ECD. Results: Covariability in CSF 5HIAA and HVA levels was observed in the total population (GDS: R = 0.470; P < 0.0001). The CSF HVA/5HIAA ratio correlated negatively with dementia severity in AD (R= -0.188; P = 0.019) and F r D patients (MMSE: R = 0.551; P = 0.004). Aggressive behavior correlated negatively (R= -0.168; P = 0.030) and apathy positively (R = 0.165; P = 0.035) with CSF 5HIAA levels in AD patients. High CSF DOPAC levels were associated with agitation and aggression in F r D patients (R = 0.533; P = 0,005) and predicted future aggressive and agitated behavior (CSF DOPAC levels > 0.5 ng/ml predicted having a CMAI total score of >40 one year later with a PPV = 1.0). The CSF HVA/5HIAA ratio correlated with aggressive behavior in FTD patients. In DLB patients, apathy (R= -0.522; P = 0.026) and the MFS score (R= -0.566; P = 0.014) correlated negatively with CSF DOPAC levels. Conclusions: The CSF HVA/5HIAA ratio reflecting tonic serotonergic modulation of dopaminergic activity, was negatively associated with dementia severity in AD and FTD patients, pointing to a non-disease specific effect of the serotonergic neurotransmitter system on cognition. This study demonstrated that the nenrochemical substrates of BPSD are disease-specific: (1) high CSF DOPAC levels were associated with agitation and aggression in FTD patients and predicted future aggressive and agitated behavior; (2) low CSF DOPAC levels were associated with increased frontal lobe symptoms like apathy in DLB patients; (3) in AD, apathy might be related to changed serotonergic activity, possibly exerting its effects through altered modulation of the dopaminergic neurotransmitter system.
~ H I G H
PLASMA INSULIN LEVELS PROVOKE INCREASES IN C E N T R A L BUT NOT P E R I P H E R A L CYTOKINE LEVELS: R E L A T I O N S H I P TO CSF AND PLASMA BETA A M Y L O I D
Mark Fishel* 1, Thomas Montine 2, Qin Wang 2, Pattie Green 2, Jake Knistad 1, G. Stennis Watson 1, Elaine Peskind I , Laura D. Baker 1, Sanjay Asthana 3, Stephen Plymate ~, David Cook 1, Suzanne Craft 1. 1University of Washington/VAPSHCS, Seattle, WA, USA; 2 University of Washington, Seattle, WA, USA; 3 University of Wisconsin, Madison, WI, USA. Contact e-mail: [email protected]
Background: In vitro and animal studies suggest that inflammation interacts with processing and deposition of A[~, a key protein linked to AD pathology. In the periphery, insulin modulates many aspects of the inflammatory network. Insulin also modulates A[~ levels by promoting its release from intracellular neuronal compartments and by inhibiting its degradation by the metalloprotease insulin degrading enzyme (IDE). Hyperinsulinemia and insulin resistance have been identified as risk factors for AD, raising the possibility that insulin-mediated effects on inflammation may contribute to this increased risk. In the present study, we examined the effects of raising peripheral insulin to levels associated with insulin resistant conditions
such as T2DM on plasma and cerebrospinal fluid (CSF) inflammatory markers and beta amyloid in 15 healthy older adults mad 7 patients with mild AD. Methods: Fasting participants received two IV infusions on separate mornings, consisting of saline, or 1 mU.kg -1 .min -1 insulin with variable dextrose to maintain fasting glucose levels. Following 90 minutes of infusion, plasma and CSF were collected. Results: Insulin increased CSF F2-isoprostane and cytokines (p < 0.01). Furthermore, insulin induced changes in plasma and CSF concentrations of both short and long species of beta amyloid (AIM0, A[~2, p < 0.05), and these changes were significantly correlated with increased F2-isoprostane and cytokine levels, as well as with CSF apolipoprotein E levels. Interestingly, no changes were observed in plasma cytokine levels. Conclusions: These resuks suggest that hyperinsulinemia associated with disorders such as T2DM provokes synchronous elevations in inflammatory markers and A[342 in the brain, thereby potentially increasing the risk of AD.
~P-3f~
SIMULTANEOUS M E A S U R E M E N T OF A[~(1-42),TAU,
PHOSPHORYLATED TAU IN CEREBROSPINAL FLUID USING T H E X M A P TM T E C H N O L O G Y Annika Olsson*. Institute of Clinical Neuroscience, Mtlndal, Sweden. Contact e-mail: [email protected]
Background: Alzheimer's disease (AD) is neurnpathologicaily characterized by abnormal accumulations of intracellular neurofibrillary tangles, extracellular amyloid plaques and neuronal degeneration. Neurofibrillary tangles and amyloid plaques are mainly composed of abnormally hyperphosphorylated tau protein (P-TAU) and the 42 amino acid long [~-amyloid peptide (A$(142)), respectively. Due to the heterogeneous aetiology of AD, a set of several biomarkers is probably required for an accurate diagnosis and discrimination from other neurological diseases. At present, quantification of A~(1-42), tan and P-TAU in cerebrospinal fluid (CSF) has shown to be useful for clinical diagnosis of AD. The microsphere-based xMAPTM technology (Luminex, Austin, Texas, US) is a multiparameter flow cytometer technique that makes it possible to simultaneously analyze several biomarkers in a single CSF sample. Objective(s): The purpose of this study was to evaluate a multipararneter microsphere-based assay for simultaneous quantification of A~(1-42), tan and P-TAU181p (a research version of the 1NNO-BIA AlzBio3, Innogenetics N.V., Gent) in CSE Methods: The xMAFT M technology was compared with ELISA methods for the same analytes. The diagnostic potentials of these molecular markers for AD were evaluated by analyzing CSF samples for A[~(1-42),tan, and P-TAU(lslP) from in 78 AD patients, 15 patient with MCI with progression to AD (MCI-AD), 53 healthy controls and 128 patients with other neurological diagnoses. Results: We showed that the xMAP TM technology provide high reproducibility and results in a diagnostic sensitivity for AD and specifcity to distinguish AD from other neurological disorders that are in the same range as for ELISA methods Conclusions: The microsphere-based xMAP TM technology provides other biological markers to be added to the xMAP TM CSF panel, which in the future might give new better tools for the clinical diagnosis of AD and other neurodegenerative disorders.
~
D E V E L O P M E N T AND VALIDATION O F HUMAN
A[342 ASSAY WITH SPECIFIC MEASUREMENT OF H U M A N A~1-42 IN NATURAL SAMPLES Jimin Wang*, Vimai Patel, Chun Ran, Lynda Zorn, Kevin Reagan. BioSource, Camarillo, CA, USA. Contact e-mail: [email protected] Alzheimer's Disease (AD) is characterized by the presence of redundant senile plaques. The major protein component of these plaques is O-amyloid peptide (A[~), a 40 to 43 amino acid peptide cleaved from amyloid precursor protein by [~-secretase (e.g., BACE) and a putative y secretase. Increased release of the 'longer forms' of A[~ peptide, A~42 or ARM3, which have a greater tendency to aggregate than AIM0, occurs in individuals expressing certain genetic mutations, expressing certain ApoE alleles, or may involve other, still undiscovered, factors. Some researchers theorize that it is this increased release of A~42/A[~43 which leads to the abnormal deposition of