- Email: [email protected]
P3-023 Salivary cortisol associated with cognitive decline in normal elderly
Poster Session 1'3: Diagnosis and Disease Progression - Blood~Plasma~Serum Markers al., JAMA 2003), CSF beta-amyloid1-42 (A131-42) below 444 pg/mL and tau protein > 195 pg/mL provide sensitivity and specificity of 92% and 89%, at least comparable to mere clinical criteria. Objectlve(s): We aimed at investigating whether these CSF markers contribute to recognize "pure" Alzheimer's (AD) vs. AD with different degree of vascular pathology. In addition, we examined the tau protein phosphorilated at threonine 181 (p-tanl81) in different forms of primary cortical dementia. Methods: 100 patients affected by mild/moderate cognitive impairment and classified as probable AD (n = 40), AD with small cerebrovascular lesions (+CVD, n = 25), Fronto-temporal dementia (FTD, n = 16), and vascular dementia (VAD, n = 19) were enrolled. In all these patients we measured the CSF concentrations of A131-42, t-tan and p-taul81. CSF was obtained by standard procedure; 1 cc was stored at -80°c until biochemical analysis was performed using a commercial sandwich enzyme-linked immunosorbent assay (ELISA, Innotest).The obtained values were also compared to an age-matched subgroup of patients with other neurological disorders (OND) without any cognitive decline (n = 28). Results: AD patients showed a peculiar pattern, characterized by low A[31-42 (mean = 172 pg/ml) and rather elevated ttau/A[31-42 ratio. In particular, low A[31-42 featured AD vs. VAD. Although t-tau did not differ between AD, FTD and VAD patients, p-taul81 resulted significantly higher in AD vs. coeval FTD patients. Amongst AD subjects, none of these markers correlated with disease duration or age at onset. Surprisingly, the concentration of A[31-42 was inversely correlated with the cognitive impairment assessed by MMSE. Iu addition, when AD patients were dissected in two subgroups (namely AD without or with CVD), significant difference failed to emerge. Conclusions: Overall, these biomarkers proved useful to further discriminate AD patients vs. other cortical dementias. More importantly, they might represent a valuable tool to improve diagnostic accuracy in clinical forms of dementia improperly defined as "mixed".
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P L A S M A AI3 L E V E L S F O L L O W I N G A[3 ANTIBODY A D M I N I S T R A T I O N IN Y O U N G M I C E P R E D I C T S BRAIN AMYLOID BURDEN AT AN O L D E R A G E
Steven M. Paul* 1, S. Wu t, C. DeLong 1, X. Wu 1, D. Holtzman 2, R. DeMattos I, K.R. Bales I. tNeuroscience Discovery Research, Indianapolis, IN, USA,"2Dept. of Neurology, Wash. Univ. School of Medicine, St. Louis, MO, USA. Contact e-mail: Paul [email protected]
Background: Previously we reported that administration of an anti-A[~ antibody; m266.2, resulted in a rapid and sustained increase in plasma A~ levels which were significantly correlated to brain A[3/amyloid burden. Objectives: To investigate whether plasma A[340 and/or AIM2 levels following a single administration of an anti-A~ antibody; m266, at a young age (4 or 8 months of age) could predict the amount of brain amyloid burden which would occur at an older age (12 months of age). Methods: Two cohorts of APP V717F transgenic mice at 4 and 8 months of age were administered a single dose of m266 (500 Izg). Twenty four hours after antibody administration, plasma AIM0 and A[342 levels were determined by ELISA. Mice were subsequently aged an additional 8 and 4 mouth, respectively. At 12 months of age, amyloid burden was determined using quantitative immunohistochemistry. Conclusions: There was a highly significant correlation between plasma A~42 and A[3 40 at 8 mouths and brain A[~ burden quantified at 12 months. Plasma A~42 levels measured in 4. month old mice following administration of m266 were significantly correlated to brain amyloid burden at 12 months of age. These data suggest that plasma A[~ levels following a single administration of m266 at a young can accurately predict the amount of brain amyloid burden that will develop as these tg mice age.
[ P3-022 ~l BIOBANKING IN AD AND RELATED DISORDERS THE AMSTERDAM E X P E R I E N C E g
Rivka Ravid*, G.J. Van Kamp, S.N.M. Schonenboom, C. Mulder, E.M. Hol, Ph. Scheltens. Netherlands Brain Bank, Amsterdam, Netherlands. Contact e-mail: [email protected] l'he definite diagnosis of Alzheimer's disease is based upon the clinical
$357
and neuropathological conformation. The determination of the diswlbution pattern and quantifying the classical pathological hallmarks is performed on autopsy-validated cases within the framework of the Netherlands Brain Bank (NBB). Since therapeutical interference can only be effective if started in an early stage of the disease, we routinely collect both ante mortem and post-mortem cerebrospinal fluid (CSF) and/or blood in the search for diagnostic markers for Alzheimer's disease. Abnormal fluctuations in CSF tan and Af342 are determined in both early and late onset cases, in sporadic and familial cases of AD. The investigated groups include validated AD cases, disease controls with other neurological conditions mad matched non-neurological controls. Post-mortem CSF is obtained by puncture of the lateral ventricles during rapid autopsies, spanned down at 5000 rpm for 10 minutes, aliquoted in tubes of 1 ml, slowly frozen and stored at -80°C. AIM2 has previously been reported to decrease in ante mortem CSF of AD cases, whereas CSF tau has been found to be elevated in AD. A large cohort of autopsy validated cases of the NBB (800) which have been genotyped for ApoE, are screened at present to check the validity of the various markers in body fluids obtained at rapid autopsy as compared to ante mortem CSF and blond. All AD patients had clinical diagnose of AD using NINCDS-ADRAD Work Group Criteria and histopathological diagnosis of AD using a combination of the CERAD criteria and the Braak staging for tan and amyloid. This will determine whether the actual values of the classical AD biomarkers are well reflected in post-mortem blood and CSF, which in turn will determine the future directions of Bit banking in AD for use in early diagnostics and the development of diagnostic tests.
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SALIVARY C O R T I S O L A S S O C I A T E D W I T H C O G N I T I V E D E C L I N E IN N O R M A L E L D E R L Y
Ge Gall Li* i, Monique Cherrier 1, Debby Tsuang 1,2, Eric Petrie 1,2, Elizabeth Colasurdo 2, Wilkinson W. Charles 1,2, Elaine Peskind t,2, Murray Raskind t,~. 1University of Washington, Seattle, WA, USA," 2VA Puget Sound Health Care System, Seattle, WA, USA. Contact e-mail: gli @u. washington, edu
Background: Previous studies have suggested that increased circulating corticosteroid concentrations, presumably by exposing the brain to excess corticosteroids, lower the threshold for hippocampal neurodegeneration and cognitive impairment. Lupien et al. (1996 and 1998) reported a longitudinal study in a small human sample and found that high plasma cortisol and increasing cortisol over time were associated with declarative memory impairment and lower hippocampal volume at end of study. Objective: To examine the association of salivary cortisol concentration with cognitive impairment in a 3-year longitudinal study. Methods: Salivary cortisol samples were collected at home at 3 different times of day (08:00, 15:00 and 23:00) at both baseline and at annual follow-ups in 79 initially cognitively intact older persons (mean age 78 4- 2, mean Mini Mental State Exam scores [MMSE] 28 -4- 2). Cognitive function tests included the MMSE, Immediate and delayed paragraph recall, Proactive interference, Stroop and Trail making test. These were assessed annually. Results: 46 subjects completed the entire 3-year study. Among these subjects, high salivary cortisol at end of study, together with increasing salivary cortisol over time were significantly associated with poorer cognitive function in tests of declarative memory as well as executive function. Furthermore, higher baseline cortisol predicted decline in performance on the delayed paragraph recall, a test of presumably hippocampally mediated declarative memory. Conclusion: These results partially confirm Lupien et al's findings that high cortisol is associated with impaired declarative memory function in older cognitively intact humans. In addition, our data show that high baseline salivary cortisol predicts decline in memory function over the next 3 years. The use of salivary cottisol collected at home eliminates the nonspecific stress of venipuncture in the laboratory setting.
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P L A S M A AI3 L E V E L S F O L L O W I N G A[3 ANTIBODY A D M I N I S T R A T I O N IN Y O U N G M I C E P R E D I C T S BRAIN AMYLOID BURDEN AT AN O L D E R A G E
Steven M. Paul* 1, S. Wu t, C. DeLong 1, X. Wu 1, D. Holtzman 2, R. DeMattos I, K.R. Bales I. tNeuroscience Discovery Research, Indianapolis, IN, USA,"2Dept. of Neurology, Wash. Univ. School of Medicine, St. Louis, MO, USA. Contact e-mail: Paul [email protected]
Background: Previously we reported that administration of an anti-A[~ antibody; m266.2, resulted in a rapid and sustained increase in plasma A~ levels which were significantly correlated to brain A[3/amyloid burden. Objectives: To investigate whether plasma A[340 and/or AIM2 levels following a single administration of an anti-A~ antibody; m266, at a young age (4 or 8 months of age) could predict the amount of brain amyloid burden which would occur at an older age (12 months of age). Methods: Two cohorts of APP V717F transgenic mice at 4 and 8 months of age were administered a single dose of m266 (500 Izg). Twenty four hours after antibody administration, plasma AIM0 and A[342 levels were determined by ELISA. Mice were subsequently aged an additional 8 and 4 mouth, respectively. At 12 months of age, amyloid burden was determined using quantitative immunohistochemistry. Conclusions: There was a highly significant correlation between plasma A~42 and A[3 40 at 8 mouths and brain A[~ burden quantified at 12 months. Plasma A~42 levels measured in 4. month old mice following administration of m266 were significantly correlated to brain amyloid burden at 12 months of age. These data suggest that plasma A[~ levels following a single administration of m266 at a young can accurately predict the amount of brain amyloid burden that will develop as these tg mice age.
[ P3-022 ~l BIOBANKING IN AD AND RELATED DISORDERS THE AMSTERDAM E X P E R I E N C E g
Rivka Ravid*, G.J. Van Kamp, S.N.M. Schonenboom, C. Mulder, E.M. Hol, Ph. Scheltens. Netherlands Brain Bank, Amsterdam, Netherlands. Contact e-mail: [email protected] l'he definite diagnosis of Alzheimer's disease is based upon the clinical
$357
and neuropathological conformation. The determination of the diswlbution pattern and quantifying the classical pathological hallmarks is performed on autopsy-validated cases within the framework of the Netherlands Brain Bank (NBB). Since therapeutical interference can only be effective if started in an early stage of the disease, we routinely collect both ante mortem and post-mortem cerebrospinal fluid (CSF) and/or blood in the search for diagnostic markers for Alzheimer's disease. Abnormal fluctuations in CSF tan and Af342 are determined in both early and late onset cases, in sporadic and familial cases of AD. The investigated groups include validated AD cases, disease controls with other neurological conditions mad matched non-neurological controls. Post-mortem CSF is obtained by puncture of the lateral ventricles during rapid autopsies, spanned down at 5000 rpm for 10 minutes, aliquoted in tubes of 1 ml, slowly frozen and stored at -80°C. AIM2 has previously been reported to decrease in ante mortem CSF of AD cases, whereas CSF tau has been found to be elevated in AD. A large cohort of autopsy validated cases of the NBB (800) which have been genotyped for ApoE, are screened at present to check the validity of the various markers in body fluids obtained at rapid autopsy as compared to ante mortem CSF and blond. All AD patients had clinical diagnose of AD using NINCDS-ADRAD Work Group Criteria and histopathological diagnosis of AD using a combination of the CERAD criteria and the Braak staging for tan and amyloid. This will determine whether the actual values of the classical AD biomarkers are well reflected in post-mortem blood and CSF, which in turn will determine the future directions of Bit banking in AD for use in early diagnostics and the development of diagnostic tests.
•
SALIVARY C O R T I S O L A S S O C I A T E D W I T H C O G N I T I V E D E C L I N E IN N O R M A L E L D E R L Y
Ge Gall Li* i, Monique Cherrier 1, Debby Tsuang 1,2, Eric Petrie 1,2, Elizabeth Colasurdo 2, Wilkinson W. Charles 1,2, Elaine Peskind t,2, Murray Raskind t,~. 1University of Washington, Seattle, WA, USA," 2VA Puget Sound Health Care System, Seattle, WA, USA. Contact e-mail: gli @u. washington, edu
Background: Previous studies have suggested that increased circulating corticosteroid concentrations, presumably by exposing the brain to excess corticosteroids, lower the threshold for hippocampal neurodegeneration and cognitive impairment. Lupien et al. (1996 and 1998) reported a longitudinal study in a small human sample and found that high plasma cortisol and increasing cortisol over time were associated with declarative memory impairment and lower hippocampal volume at end of study. Objective: To examine the association of salivary cortisol concentration with cognitive impairment in a 3-year longitudinal study. Methods: Salivary cortisol samples were collected at home at 3 different times of day (08:00, 15:00 and 23:00) at both baseline and at annual follow-ups in 79 initially cognitively intact older persons (mean age 78 4- 2, mean Mini Mental State Exam scores [MMSE] 28 -4- 2). Cognitive function tests included the MMSE, Immediate and delayed paragraph recall, Proactive interference, Stroop and Trail making test. These were assessed annually. Results: 46 subjects completed the entire 3-year study. Among these subjects, high salivary cortisol at end of study, together with increasing salivary cortisol over time were significantly associated with poorer cognitive function in tests of declarative memory as well as executive function. Furthermore, higher baseline cortisol predicted decline in performance on the delayed paragraph recall, a test of presumably hippocampally mediated declarative memory. Conclusion: These results partially confirm Lupien et al's findings that high cortisol is associated with impaired declarative memory function in older cognitively intact humans. In addition, our data show that high baseline salivary cortisol predicts decline in memory function over the next 3 years. The use of salivary cottisol collected at home eliminates the nonspecific stress of venipuncture in the laboratory setting.