- Email: [email protected]
Magnetic resonance biomarkers of neurodegeneration in a transgenic mouse model of Alzheimer's disease
Poster Presentations P3 P3-251
MAGNETIC RESONANCE BIOMARKERS OF NEURODEGENERATION IN A TRANSGENIC MOUSE MODEL OF ALZHEIMER’S DISEASE
Malgorzata Marjanska1, R. Chamberlain1, G. Preboske2, A. Polk1, L. Kotilinek1, T. M. Wengenack2, J. F. Poduslo2, S. A. Youdas2, K. H. Ashe1, M. Garwood1, C. R. Jack, Jr.,2, 1University of Minneapolis, Minneapolis, MN, USA; 2Mayo Clinic, Rochester, MN, USA. Contact e-mail: [email protected] Background: The histological abnormalities that characterize Alzheimer’s disease (AD) are commonly divided into four major classes: amyloid plaques, neurofibrillary tangles, inflammation, and neurodegeneration (NDG). In this work we compare the ability of various MR techniques (volume, T1r, T2r, ADC, FA) to detect the NDG in the rTg4510 mouse model (1) compared to wild-type (WT) mice. Methods: In vivo experiments were performed using a 9.4-T/31-cm horizontal bore magnet equipped with a Varian INOVA spectrometer. rTg4510 mice over express mutant human tau leading to an induced tauopathy and extensive neurodegeneration by 9 months of age. Four Tg4510 mice were imaged at 13 months of age and four WT mice were imaged at 12 months of age. All images were acquired using a quadrature surface coil. The volume image was acquired with a 3D multi-asymmetric spin-echo pulse sequence (2) with resolution 120 mm x 120 mm x 400 mm. The apparent diffusion coefficient (ADC) and fractional anisotropy (FA) and the rotating frame relaxation times, T1r and T2r, were measured with a 2D single slice with in-plane resolution of 80 mm x 80 mm, slice thickness of 1 mm. Results: All MR techniques detected the expected differences between WT and rTg4510 mice as shown in the table.
autopsy confirmation. Levels of CSF biomarkers may also track cognitive decline during disease progression, and their levels may be considered secondary endpoints in future therapeutic trials. Objective: To identify antemortem cerebrospinal fluid (CSF) diagnostic biomarkers that distinguish pathologically confirmed AD from cognitively normal (NL) subjects and patients with other neurodegenerative disorders such as frontotemporal lobar degeneration and dementia with Lewy bodies, and CSF biomarkers that correlate with cognition in AD and mild cognitive impairment (MCI). Methods: CSF samples were collected antemortem from 66 AD patients with AD and 25 patients with other neurodegenerative dementias followed longitudinally to neuropathologic confirmation, 42 longitudinally followed MCI patients, and 33 NL. Levels of 151 novel analytes were measured via a targeted multiplex panel enriched in cytokines, chemokines, and growth factors as well as established AD biomarkers (ApoE4 allele, and levels of Ab42, tau, and ptau181). Results: AD is best distinguished from NL by a combination of traditional AD biomarkers that confer sensitivity, and multiplex biomarkers that confer specificity relative to NL. Two categories of biomarkers were identified: 1) analytes that specifically distinguish AD (especially CSF Ab42 levels) from NL and other neurodegenerative disorders; and 2) analytes altered in multiple neurodegenerative diseases, but not in NL subjects. Six analytes were correlated with severity of cognitive impairment at CSF collection, and two were associated with subsequent cognitive decline in MCI. Conclusions: Our targeted proteomic screen revealed novel CSF biomarkers that distinguished AD from NL and other neurodegenerative disorders, and subsets of biomarkers that correlated with cognition and subsequent cognitive decline. A multiplex panel of CSF biomarkers can improve the antemortem diagnostic and prognostic classification of AD and MCI. P3-253
Volume (mm3) FA
Detecting lower - neuronal loss lower - loss of white matter tract integrity higher - neuronal loss
Hippocampus
Corpus Callosum
WT 28.9 6 0.9
WT –
–
Tg4510 23 6 1 –
1.44 6 0.01 1.66 6 ADC 0.03 (mm2/s x 10L3) 95.3 6 0.8 105 6 2 T1r (ms) higher - decrease in protein-water interaction T2r (ms) higher - decrease 42.9 6 0.1 46.6 6 in protein-water 0.6 interaction
Tg4510 –
0.73 6 0.01 0.63 6 0.01
–
83.3 6 0.4
39.5 6 0.2
–
89.8 6 0.5
41.5 6 0.3
Conclusions: These results show that NDG can be detected with various measurements in transgenic mice over expressing mutant human tau. These techniques are all in theory candidate biomarkers for human AD and could enhance diagnostic sensitivity and aid in early diagnosis of AD in humans. References [1] SantaCruz K, et al, Science 309: 476 (1998), [2] Chamberlain R, et al, MRM 61: 1158 (2009). P3-252
NOVEL CSF BIOMARKERS FOR ALZHEIMER’S DISEASE AND MILD COGNITIVE IMPAIRMENT
William T. Hu1,2, Alice Chen-Plotkin1, Steven E. Arnold1, Murray Grossman1, Christopher M. Clark1, Leslie M. Shaw1, Virginia M.Y. Lee1, Holly D. Soares3, John Q. Trojanowski1, 1University of Pennsylvania, Philadelphia, PA, USA; 2Emory University, Atlanta, GA, USA; 3Pfizer Global Research and Development, Groton, CT, USA. Contact e-mail: [email protected] Background: The accuracy of biomarkers for Alzheimer’s disease (AD) can be best determined in well-characterized patients longitudinally followed to
S525
CHANGES IN AB42 LEVELS ARE ASSOCIATED WITH THE FUNCTIONAL OUTCOME IN ALZHEIMER’S DISEASE
Anton Alvarez1, Carolina Sampedro1, Veronica Couceiro1, Ramon Cacabelos1, Manuel Aleixandre2, Carlos Linares3, Elias Granizo3, Herbert Moessler4, Manfred Windisch5, Markus Mandler6, Frank Mattner6, 1 Euroespes Biomedical Research Centre, A Corun˜a, Spain; 2Faculty of Psychology, Granada University, Granada, Spain; 3Memory Clinic, Malaga, Spain; 4Ever Neuro Pharma, Unterach, Austria; 5JSW Life Sciences, Grambach, Austria; 6Affiris AG, Vienna, Austria. Contact e-mail: [email protected] Background: Amyloid-beta (AB) is the main pathogenic factor in Alzheimer’s disease (AD). Reductions of the AB42 fragment in the cerebrospinal fluid (CSF) are of diagnostic value and correlate with AD severity. However, there are no clear clues for the interpretation of changes in plasma and CSF AB42 levels after therapeutic interventions. Methods: We evaluated AB42 levels in two different sets of AD patients completing per protocol two randomized clinical trials: (1) 158 patients treated during 28 weeks with Cerebrolysin 10mL, Donepezil-10mg or a combination of both; and (2) 54 patients receiving either placebo, 20mg or 30mg of Phenserine tartrate for 24 weeks. Samples of plasma (both studies) and CSF (second trial only) were obtained at baseline and after treatment. Changes in cognition (ADAScog+ scores), functioning in activities of daily living (ADCS-ADL scores) and neuropsychiatric symptoms (NPI scores) were compared between patients showing reductions and those undergoing increases in AB42 levels from baseline. Results: Independently of the treatment received, patients with decreases in plasma AB42 showed a significant improvement of functioning (p < 0.01) as compared to those with AB42 elevations. On the contrary, increases in CSF AB42 levels were associated with a better functional outcome (p < 0.01) in AD patients. No significant differences were found between the two AB42-response groups for changes in cognitive performace or behavior in any study. Conclusions: These results indicate that reductions in plasma AB42 and/or increases in CSF AB42 levels are associated with a better functioning in activities of daily living after treatment with neurotrophic and/or cholinergic drugs in AD patients. If there is a direct link between changes in plasma/CSF AB42 and functional improvement, or if both facts are merely a reflect of an improved general condition of the patients merits further investigation.
MAGNETIC RESONANCE BIOMARKERS OF NEURODEGENERATION IN A TRANSGENIC MOUSE MODEL OF ALZHEIMER’S DISEASE
Malgorzata Marjanska1, R. Chamberlain1, G. Preboske2, A. Polk1, L. Kotilinek1, T. M. Wengenack2, J. F. Poduslo2, S. A. Youdas2, K. H. Ashe1, M. Garwood1, C. R. Jack, Jr.,2, 1University of Minneapolis, Minneapolis, MN, USA; 2Mayo Clinic, Rochester, MN, USA. Contact e-mail: [email protected] Background: The histological abnormalities that characterize Alzheimer’s disease (AD) are commonly divided into four major classes: amyloid plaques, neurofibrillary tangles, inflammation, and neurodegeneration (NDG). In this work we compare the ability of various MR techniques (volume, T1r, T2r, ADC, FA) to detect the NDG in the rTg4510 mouse model (1) compared to wild-type (WT) mice. Methods: In vivo experiments were performed using a 9.4-T/31-cm horizontal bore magnet equipped with a Varian INOVA spectrometer. rTg4510 mice over express mutant human tau leading to an induced tauopathy and extensive neurodegeneration by 9 months of age. Four Tg4510 mice were imaged at 13 months of age and four WT mice were imaged at 12 months of age. All images were acquired using a quadrature surface coil. The volume image was acquired with a 3D multi-asymmetric spin-echo pulse sequence (2) with resolution 120 mm x 120 mm x 400 mm. The apparent diffusion coefficient (ADC) and fractional anisotropy (FA) and the rotating frame relaxation times, T1r and T2r, were measured with a 2D single slice with in-plane resolution of 80 mm x 80 mm, slice thickness of 1 mm. Results: All MR techniques detected the expected differences between WT and rTg4510 mice as shown in the table.
autopsy confirmation. Levels of CSF biomarkers may also track cognitive decline during disease progression, and their levels may be considered secondary endpoints in future therapeutic trials. Objective: To identify antemortem cerebrospinal fluid (CSF) diagnostic biomarkers that distinguish pathologically confirmed AD from cognitively normal (NL) subjects and patients with other neurodegenerative disorders such as frontotemporal lobar degeneration and dementia with Lewy bodies, and CSF biomarkers that correlate with cognition in AD and mild cognitive impairment (MCI). Methods: CSF samples were collected antemortem from 66 AD patients with AD and 25 patients with other neurodegenerative dementias followed longitudinally to neuropathologic confirmation, 42 longitudinally followed MCI patients, and 33 NL. Levels of 151 novel analytes were measured via a targeted multiplex panel enriched in cytokines, chemokines, and growth factors as well as established AD biomarkers (ApoE4 allele, and levels of Ab42, tau, and ptau181). Results: AD is best distinguished from NL by a combination of traditional AD biomarkers that confer sensitivity, and multiplex biomarkers that confer specificity relative to NL. Two categories of biomarkers were identified: 1) analytes that specifically distinguish AD (especially CSF Ab42 levels) from NL and other neurodegenerative disorders; and 2) analytes altered in multiple neurodegenerative diseases, but not in NL subjects. Six analytes were correlated with severity of cognitive impairment at CSF collection, and two were associated with subsequent cognitive decline in MCI. Conclusions: Our targeted proteomic screen revealed novel CSF biomarkers that distinguished AD from NL and other neurodegenerative disorders, and subsets of biomarkers that correlated with cognition and subsequent cognitive decline. A multiplex panel of CSF biomarkers can improve the antemortem diagnostic and prognostic classification of AD and MCI. P3-253
Volume (mm3) FA
Detecting lower - neuronal loss lower - loss of white matter tract integrity higher - neuronal loss
Hippocampus
Corpus Callosum
WT 28.9 6 0.9
WT –
–
Tg4510 23 6 1 –
1.44 6 0.01 1.66 6 ADC 0.03 (mm2/s x 10L3) 95.3 6 0.8 105 6 2 T1r (ms) higher - decrease in protein-water interaction T2r (ms) higher - decrease 42.9 6 0.1 46.6 6 in protein-water 0.6 interaction
Tg4510 –
0.73 6 0.01 0.63 6 0.01
–
83.3 6 0.4
39.5 6 0.2
–
89.8 6 0.5
41.5 6 0.3
Conclusions: These results show that NDG can be detected with various measurements in transgenic mice over expressing mutant human tau. These techniques are all in theory candidate biomarkers for human AD and could enhance diagnostic sensitivity and aid in early diagnosis of AD in humans. References [1] SantaCruz K, et al, Science 309: 476 (1998), [2] Chamberlain R, et al, MRM 61: 1158 (2009). P3-252
NOVEL CSF BIOMARKERS FOR ALZHEIMER’S DISEASE AND MILD COGNITIVE IMPAIRMENT
William T. Hu1,2, Alice Chen-Plotkin1, Steven E. Arnold1, Murray Grossman1, Christopher M. Clark1, Leslie M. Shaw1, Virginia M.Y. Lee1, Holly D. Soares3, John Q. Trojanowski1, 1University of Pennsylvania, Philadelphia, PA, USA; 2Emory University, Atlanta, GA, USA; 3Pfizer Global Research and Development, Groton, CT, USA. Contact e-mail: [email protected] Background: The accuracy of biomarkers for Alzheimer’s disease (AD) can be best determined in well-characterized patients longitudinally followed to
S525
CHANGES IN AB42 LEVELS ARE ASSOCIATED WITH THE FUNCTIONAL OUTCOME IN ALZHEIMER’S DISEASE
Anton Alvarez1, Carolina Sampedro1, Veronica Couceiro1, Ramon Cacabelos1, Manuel Aleixandre2, Carlos Linares3, Elias Granizo3, Herbert Moessler4, Manfred Windisch5, Markus Mandler6, Frank Mattner6, 1 Euroespes Biomedical Research Centre, A Corun˜a, Spain; 2Faculty of Psychology, Granada University, Granada, Spain; 3Memory Clinic, Malaga, Spain; 4Ever Neuro Pharma, Unterach, Austria; 5JSW Life Sciences, Grambach, Austria; 6Affiris AG, Vienna, Austria. Contact e-mail: [email protected] Background: Amyloid-beta (AB) is the main pathogenic factor in Alzheimer’s disease (AD). Reductions of the AB42 fragment in the cerebrospinal fluid (CSF) are of diagnostic value and correlate with AD severity. However, there are no clear clues for the interpretation of changes in plasma and CSF AB42 levels after therapeutic interventions. Methods: We evaluated AB42 levels in two different sets of AD patients completing per protocol two randomized clinical trials: (1) 158 patients treated during 28 weeks with Cerebrolysin 10mL, Donepezil-10mg or a combination of both; and (2) 54 patients receiving either placebo, 20mg or 30mg of Phenserine tartrate for 24 weeks. Samples of plasma (both studies) and CSF (second trial only) were obtained at baseline and after treatment. Changes in cognition (ADAScog+ scores), functioning in activities of daily living (ADCS-ADL scores) and neuropsychiatric symptoms (NPI scores) were compared between patients showing reductions and those undergoing increases in AB42 levels from baseline. Results: Independently of the treatment received, patients with decreases in plasma AB42 showed a significant improvement of functioning (p < 0.01) as compared to those with AB42 elevations. On the contrary, increases in CSF AB42 levels were associated with a better functional outcome (p < 0.01) in AD patients. No significant differences were found between the two AB42-response groups for changes in cognitive performace or behavior in any study. Conclusions: These results indicate that reductions in plasma AB42 and/or increases in CSF AB42 levels are associated with a better functioning in activities of daily living after treatment with neurotrophic and/or cholinergic drugs in AD patients. If there is a direct link between changes in plasma/CSF AB42 and functional improvement, or if both facts are merely a reflect of an improved general condition of the patients merits further investigation.