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Cystatin C as biological marker in mild cognitive impairment predicting for VAD
Abstracts: Biomarkers / 1 (Suppl 1) (2005) P-019
PLASMA AMYLOID BETA PROTEIN 42 IN NONDEMENTED PERSONS AGED 75-YEARS: EFFECTS OF CONCOMITANT MEDICATION AND MEDIAL TEMPORAL LOBE ATROPHY
Imrich Blasko1, Joerg Kemmler1, Wolfgang Krampla2,3, Susanne Jungwirt4, Ildigo Wichard5, Kurt Jellinger5, Karl Heinz Tragl4, Peter Fischer4,6; 1Medical University of Innsbruck, Dept. of Psychiatry, Innsbruck, Austria; 2Danube Hospita, Vienna, Austria; 3L. Boltzmann Institute of Digital Radiology and Interventional Radiology, Vienna, Austria; 4Ludwig Boltzmann Institute of Aging Research, Vienna, Austria; 5Institute of Clinical Neurobiology, Vienna, Austria; 6Medical University of Vienna, Dept. of Psychiatry, Vienna, Austria Background: Plasma amyloid beta 42 (Abeta42) levels increase with age and are elevated in some patients during the early stages of Alzheimer’s disease (AD). Although plasma Abeta42 is not useful for diagnosis of AD, it might be a biological risk factor. In the elderly population a considerable variety of concomitant medication is used for the treatment of various disorders. Objective(s): To investigate how co-medication might influence Abeta42 plasma levels. Methods: Through the Vienna Transdanube Aging study (VITA), the authors measured cross-sectional Abeta42 plasma levels during the initial examination of 526 individuals aged 75 years without dementia. The medication considered included treatment with calcium channel blockers, digitalis, anticoagulants, antihistamines, ergotamine, histamine H2 receptor antagonists, bronchodilators, pentoxyfilline, neuroleptics, insulin, oral antidiabetics, L-dopa, benzodiazepines, oestrogen, Gingko biloba, vitamins, piracetam, non-steroidal anti-inflammatory drugs (NSAIDs), and statins. Conclusions: Of the study population aged 75 years, 90% were users of some of the above mentioned medication. Depending on their medial temporal lobe atrophy (MTA), users of insulin showed significantly increased levels of Abeta42, while users of gingko biloba longer than two years had significantly decreased Abeta42 plasma levels, independent of their MTA. Users of statins and NSAIDs showed a non-significant trend to reduced Abeta42 plasma levels, while users of biguanides showed an increase in Abeta42 plasma levels. Persons with a low degree of MTA had significantly increased Abeta42 plasma levels. Considering the increase of Abeta42 plasma levels as a risk factor for AD, any changes induced by medication by long term use in the peripheral and possibly also in the central compartment, could be of clinical relevance. P-020
P300 (LATENCY) EVENT-RELATED POTENTIAL: AN ACCURATE PREDICTOR OF MEMORY IMPAIRMENT : HORMONAL CORRELATES
Eric R. Braverman1, Kenneth Blum1,2; 1Path Foundation, NY, NY, USA; 2 Department of Pharmacology Wake Forest University School of Medicine, Winston-Salem, NC, USA Background: To identify objective bioelectrical markers of early memory impairment because after age 60, the incidence of dementia doubles every 5 years. Objective: To determine if P300 latency changes precede and correlate to memory, MMSE, and hormonal changes in a population from 20 to 100 years. Methods: Patients (N⫽1506) received medical/psychiatric diagnoses (from 1997 to 2002), and P300 (N⫽1496), WMS-III (N⫽694), and MMSE (N⫽456) testing. Control groups included, a) normal WMS-III on 4 subscales (N⫽36), b) normal WMS-III and MMSE (N⫽189) with subjective memory/mental status complaints c) medical patients with normal WMS-III and no memory complaints (N⫽205) and P300 control group without medical, psychiatric or memory problems for ROC. Hormonal measurements were acquired in 1,372 subjects. Conclusion: Patients with impaired/borderline memory have prolonged P300 latency (P⬍0.02) compared to age matched non-impaired controls. Patients with normal WMS-III/MMSE, with subjective mild memory/mental status complaints, have prolonged P300 latency compared to controls (P⫽0.0004). P300 latency increased by 0.72ms per year (P⫽7.9x10-65) and voltage decreased by 0.03dV per year (P⫽6.7x10-10). Both parameters are linearly correlated with the age of the subjects. Prolonged latency began at
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age 41-50 (P⫽0.0002); reduced P300 voltage began at age 51-60 (P⫽0.003); WMS-III memory decline began in females at age 61-70 (P value at least⫽0.02) and males age 61-80 (P⫽0.02); prolonged P300 latency (P⬍0.0001) and memory impairment (at least ⬍0.02) was greater for females. Male and female MMSE decline began age 81-90 (P ⬍ 0.00007). Logistic regression showed P300 latency was more predictive of WMS-III impairment than MMSE ⬎24. Patients whose WMS-III score is impaired ⱕ69, or borderline ⱕ79 (P at least ⫽0.004), were identified by prolonged P300 latency (ⱖ300 ⫹ 30 ⫹ Age) ; MMSE ⬎24 failed. ROC curve confirmed P300 latency could accurately identify borderline/impaired WMS-III scores. Furthermore, prolonged P300 latency, in males was correlated with low IGF-1 for patients aged 30-49, (p⬍0.001);low IGF-3 40-49 (p⬍0.04); low free testosterone 30-49 (p⬍0.005): low DHEA 50-69 (p⬍0.04): in females prolonged P300 latency corrrelated with low IGF-3 30-59 (p⬍0.005) ; low DHEA 40-69 (p⬍0.05).Endocrine and electrophysiological markers may need to be included in evaluating the progression from MCI to dementia. P-021
CYSTATIN C AS BIOLOGICAL MARKER IN MILD COGNITIVE IMPAIRMENT PREDICTING FOR VAD
Roberta Ghidoni, Luisa Benussi, Aldo Villa, Simona Signorini, Anna Paterlini, Francesca Nicosia, Laura Barbiero, Giuliano Binetti; Neurobiology Lab-Memory Clinic IRCCS FBF, Brescia, Italy Background: Nowadays, there are no consistence evidences of the existence of a biological marker for Mild Cognitive Impairment (MCI) able to indicate the course of cognitive deficits. Cystatin C (Cys C) has been already studied as possible biological marker in the cerebrospinal fluid (CSF) in which the protein concentration increases in patients with Vascular Dementia (VAD) when compared to Alzheimer disease subjects (AD) and controls. Nevertheless, this finding was not confirmed at peripheral levels. Objective(s): to investigate the plasma levels of Cys C as putative biological marker for dementias (AD and VAD) and for MCI. Methods: Forty-eight patients with MCI (28 of vascular type-vMCI and 20 of amnesic type-aMCI), 26 with VAD, 34 with AD and 24 CTR were included. Cys C concentration [Cys C] in plasma samples was evaluated using ELISA test. Conclusions: compared with CTR, mean [Cys C] was increased in patients with MCI (p⬍0.05). A cut-off score of 2.3 mg/L separate MCI from CTR with 70% of sensitivity and 68% of specificity. Moreover, [Cys C] in VAD were significantly higher than AD (p⬍0.0001); a cutoff score of 1.7 mg/L separated VAD from AD with 95% of specificity and 85% of sensitivity. [Cys C] in vMCI is increased as compared to aMCI (p⬍0.001). A cutoff of 3.1 mg/L separated vMCI from aMCI patients with 70% of specificity and 60% of sensitivity. Cys C could be used as specific marker able to identify cognitive decline, distinguish the cognitive decline between amnesic and vascular type and also make a distinction between VAD and AD diagnosis. Longitudinal studies are now needed to investigate if Cys C could be also a prognostic marker predicting the conversion to VAD. P-022
A BIOMARKERS AND ALZHEIMER’S DISEASE KNOWLEDGE DISCOVERY TOOL
Sherrilynne S. Fuller, Debra Revere; University of Washington, Seattle, WA, USA Background: Scientists everywhere are struggling to keep up with the latest published research studies, data pouring out of laboratories--those down the hall and across the world--as well as the vital content of numerous genomics and proteomics databases. A further problem facing researchers is the need to find, and assimilate complex research findings, biological pathways, protein structure resources, and genomics information. These problems are especially pressing for Alzheimer’s Disease (AD) researchers where the critical findings may come from bench research, clinical trials or from seemingly unrelated animal research studies. Objective(s): The goal of the present work is to develop time-saving tools that
PLASMA AMYLOID BETA PROTEIN 42 IN NONDEMENTED PERSONS AGED 75-YEARS: EFFECTS OF CONCOMITANT MEDICATION AND MEDIAL TEMPORAL LOBE ATROPHY
Imrich Blasko1, Joerg Kemmler1, Wolfgang Krampla2,3, Susanne Jungwirt4, Ildigo Wichard5, Kurt Jellinger5, Karl Heinz Tragl4, Peter Fischer4,6; 1Medical University of Innsbruck, Dept. of Psychiatry, Innsbruck, Austria; 2Danube Hospita, Vienna, Austria; 3L. Boltzmann Institute of Digital Radiology and Interventional Radiology, Vienna, Austria; 4Ludwig Boltzmann Institute of Aging Research, Vienna, Austria; 5Institute of Clinical Neurobiology, Vienna, Austria; 6Medical University of Vienna, Dept. of Psychiatry, Vienna, Austria Background: Plasma amyloid beta 42 (Abeta42) levels increase with age and are elevated in some patients during the early stages of Alzheimer’s disease (AD). Although plasma Abeta42 is not useful for diagnosis of AD, it might be a biological risk factor. In the elderly population a considerable variety of concomitant medication is used for the treatment of various disorders. Objective(s): To investigate how co-medication might influence Abeta42 plasma levels. Methods: Through the Vienna Transdanube Aging study (VITA), the authors measured cross-sectional Abeta42 plasma levels during the initial examination of 526 individuals aged 75 years without dementia. The medication considered included treatment with calcium channel blockers, digitalis, anticoagulants, antihistamines, ergotamine, histamine H2 receptor antagonists, bronchodilators, pentoxyfilline, neuroleptics, insulin, oral antidiabetics, L-dopa, benzodiazepines, oestrogen, Gingko biloba, vitamins, piracetam, non-steroidal anti-inflammatory drugs (NSAIDs), and statins. Conclusions: Of the study population aged 75 years, 90% were users of some of the above mentioned medication. Depending on their medial temporal lobe atrophy (MTA), users of insulin showed significantly increased levels of Abeta42, while users of gingko biloba longer than two years had significantly decreased Abeta42 plasma levels, independent of their MTA. Users of statins and NSAIDs showed a non-significant trend to reduced Abeta42 plasma levels, while users of biguanides showed an increase in Abeta42 plasma levels. Persons with a low degree of MTA had significantly increased Abeta42 plasma levels. Considering the increase of Abeta42 plasma levels as a risk factor for AD, any changes induced by medication by long term use in the peripheral and possibly also in the central compartment, could be of clinical relevance. P-020
P300 (LATENCY) EVENT-RELATED POTENTIAL: AN ACCURATE PREDICTOR OF MEMORY IMPAIRMENT : HORMONAL CORRELATES
Eric R. Braverman1, Kenneth Blum1,2; 1Path Foundation, NY, NY, USA; 2 Department of Pharmacology Wake Forest University School of Medicine, Winston-Salem, NC, USA Background: To identify objective bioelectrical markers of early memory impairment because after age 60, the incidence of dementia doubles every 5 years. Objective: To determine if P300 latency changes precede and correlate to memory, MMSE, and hormonal changes in a population from 20 to 100 years. Methods: Patients (N⫽1506) received medical/psychiatric diagnoses (from 1997 to 2002), and P300 (N⫽1496), WMS-III (N⫽694), and MMSE (N⫽456) testing. Control groups included, a) normal WMS-III on 4 subscales (N⫽36), b) normal WMS-III and MMSE (N⫽189) with subjective memory/mental status complaints c) medical patients with normal WMS-III and no memory complaints (N⫽205) and P300 control group without medical, psychiatric or memory problems for ROC. Hormonal measurements were acquired in 1,372 subjects. Conclusion: Patients with impaired/borderline memory have prolonged P300 latency (P⬍0.02) compared to age matched non-impaired controls. Patients with normal WMS-III/MMSE, with subjective mild memory/mental status complaints, have prolonged P300 latency compared to controls (P⫽0.0004). P300 latency increased by 0.72ms per year (P⫽7.9x10-65) and voltage decreased by 0.03dV per year (P⫽6.7x10-10). Both parameters are linearly correlated with the age of the subjects. Prolonged latency began at
S15
age 41-50 (P⫽0.0002); reduced P300 voltage began at age 51-60 (P⫽0.003); WMS-III memory decline began in females at age 61-70 (P value at least⫽0.02) and males age 61-80 (P⫽0.02); prolonged P300 latency (P⬍0.0001) and memory impairment (at least ⬍0.02) was greater for females. Male and female MMSE decline began age 81-90 (P ⬍ 0.00007). Logistic regression showed P300 latency was more predictive of WMS-III impairment than MMSE ⬎24. Patients whose WMS-III score is impaired ⱕ69, or borderline ⱕ79 (P at least ⫽0.004), were identified by prolonged P300 latency (ⱖ300 ⫹ 30 ⫹ Age) ; MMSE ⬎24 failed. ROC curve confirmed P300 latency could accurately identify borderline/impaired WMS-III scores. Furthermore, prolonged P300 latency, in males was correlated with low IGF-1 for patients aged 30-49, (p⬍0.001);low IGF-3 40-49 (p⬍0.04); low free testosterone 30-49 (p⬍0.005): low DHEA 50-69 (p⬍0.04): in females prolonged P300 latency corrrelated with low IGF-3 30-59 (p⬍0.005) ; low DHEA 40-69 (p⬍0.05).Endocrine and electrophysiological markers may need to be included in evaluating the progression from MCI to dementia. P-021
CYSTATIN C AS BIOLOGICAL MARKER IN MILD COGNITIVE IMPAIRMENT PREDICTING FOR VAD
Roberta Ghidoni, Luisa Benussi, Aldo Villa, Simona Signorini, Anna Paterlini, Francesca Nicosia, Laura Barbiero, Giuliano Binetti; Neurobiology Lab-Memory Clinic IRCCS FBF, Brescia, Italy Background: Nowadays, there are no consistence evidences of the existence of a biological marker for Mild Cognitive Impairment (MCI) able to indicate the course of cognitive deficits. Cystatin C (Cys C) has been already studied as possible biological marker in the cerebrospinal fluid (CSF) in which the protein concentration increases in patients with Vascular Dementia (VAD) when compared to Alzheimer disease subjects (AD) and controls. Nevertheless, this finding was not confirmed at peripheral levels. Objective(s): to investigate the plasma levels of Cys C as putative biological marker for dementias (AD and VAD) and for MCI. Methods: Forty-eight patients with MCI (28 of vascular type-vMCI and 20 of amnesic type-aMCI), 26 with VAD, 34 with AD and 24 CTR were included. Cys C concentration [Cys C] in plasma samples was evaluated using ELISA test. Conclusions: compared with CTR, mean [Cys C] was increased in patients with MCI (p⬍0.05). A cut-off score of 2.3 mg/L separate MCI from CTR with 70% of sensitivity and 68% of specificity. Moreover, [Cys C] in VAD were significantly higher than AD (p⬍0.0001); a cutoff score of 1.7 mg/L separated VAD from AD with 95% of specificity and 85% of sensitivity. [Cys C] in vMCI is increased as compared to aMCI (p⬍0.001). A cutoff of 3.1 mg/L separated vMCI from aMCI patients with 70% of specificity and 60% of sensitivity. Cys C could be used as specific marker able to identify cognitive decline, distinguish the cognitive decline between amnesic and vascular type and also make a distinction between VAD and AD diagnosis. Longitudinal studies are now needed to investigate if Cys C could be also a prognostic marker predicting the conversion to VAD. P-022
A BIOMARKERS AND ALZHEIMER’S DISEASE KNOWLEDGE DISCOVERY TOOL
Sherrilynne S. Fuller, Debra Revere; University of Washington, Seattle, WA, USA Background: Scientists everywhere are struggling to keep up with the latest published research studies, data pouring out of laboratories--those down the hall and across the world--as well as the vital content of numerous genomics and proteomics databases. A further problem facing researchers is the need to find, and assimilate complex research findings, biological pathways, protein structure resources, and genomics information. These problems are especially pressing for Alzheimer’s Disease (AD) researchers where the critical findings may come from bench research, clinical trials or from seemingly unrelated animal research studies. Objective(s): The goal of the present work is to develop time-saving tools that