- Email: [email protected]
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Poster P2:: Monday Posters LONGITUDINAL QUANTITATIVE MRI R2 RELAXOMETRY IN ELDERLY PARTICIPANTS REPORTING MEMORY LOSS: A USEFUL TOOL FOR THE MONITORING OF DEMENTIA ONSET?
Jonathan K. Foster1,2, Michael J. House3, Timothy G. St Pierre3, Ralph N. Martins1, Roger Clarnette4, Jodie Ricci5, 1Edith Cowan University, Joondalup, Australia; 2Neurosciences Unit, Mt Claremont, Australia; 3University of Western Australia, Crawley, Australia; 4 Department of Geriatric Medicine, Fremantle Hospital, Australia; 5 SKG Radiology, Subiaco, Australia. Contact e-mail: [email protected] Background: Magnetic resonance imaging (MRI) can be applied as a useful, non-invasive tool for characterizing, in vivo, the neurological changes associated with age-related memory loss and dementia. The transverse proton relaxation rate, R2, is an MRI parameter affected by changes in both brain iron concentration and water content. Objective(s): The objective of this pilot study was to assess longitudinal changes in R2 measured in elderly participants with mild-severe levels of cognitive impairment, and to determine the degree to which any changes in R2 signal over time were associated with changes in cognitive functioning. Methods: Six elderly participants reporting memory problems underwent two 1.5T MRI scans 12 to 24 months apart, with neuropsychological testing taking place in close temporal proximity to the scans outside the magnet. R2 data were collected from 14 brain regions in all participants. Correlations between annualized percentage changes in R2 values and annualized changes in cognitive scores were assessed. Conclusions: There were significant negative correlations between cognitive changes and R2 changes in the right temporal cortex and left hippocampus. In contrast, there were significant positive correlations between cognitive changes and R2 changes in the left temporal and parahippocampal cortex and in the right internal capsule, thalamus and putamen. These findings suggest that in vivo quantitative changes in R2 may be capable of characterizing neurological processes associated with age-related cognitive decline. Specifically, this technique may offer a useful tool for the monitoring of neurocognitive changes associated with the onset of dementia. P2-289
IN-VIVO MRI DETECTABLE THALAMIC AMYLOID-ASSOCIATED AGGREGATES DEVELOPED BY MUTATED APP/PS1 TRANSGENIC MICE: WHAT ARE THEY?
Benoıˆt Delatour1, Marc Dhenain2,3, Ting-Di Wu3, Nadine El Tannir El Tayara3, Andreas Volk3, Carmen Quintana4, 1 NAMC, CNRS UMR 8620, Orsay, France; 2URA CEA - CNRS 2210, Orsay, France; 3U759 INSERM / Institut Curie, Orsay, France; 4IMM, CSIC, Madrid, Spain. Contact e-mail: [email protected] Background/Objectives: Several transgenic mouse lines modelling Alzheimer’s brain amyloidosis were recently diagnosed with in-vivo MRI-detected localized thalamic lesions described as hypointense spots. We replicated these observations in an APP/PS1 model (Delatour et al, Neurob. Aging, 2006) and tried to assess the nature and origin of such brain alterations. Methods: Brains from transgenics with or without thalamic spots were processed for extended neuropathological examination including (immuno-)histochemical, ultrastructural (EM) and elemental (X-rays, nanoSIMS) analysis. Results: Matching MRI-detected spots topography, crystal-like aggregates were found in ventral/ posterior thalamic nuclei associated with dense peripheral microglial activation. These lesions were closely associated with amyloid plaques and, as demonstrated by complementary analysis, were characterized as mineral deposits with iron content. Levels of inflammation surrounding these thalamic aggregates did not differ from microgliosis classically observed surrounding A plaques. No sign of microhemorrhage nor abnormal vasculature were observed in APP/PS1 mice with thalamic aggregates. Lack of vascular impairment was further supported by
negative findings from in-vivo MR angiography. We finally addressed the occurrence of focal neurodegenerative processes that may be linked or explain the occurrence of localized thalamic brain lesions. Conclusion: Constancy of MRI-detected thalamic lesions in different monogenic and bigenic transgenic mice developing A brain deposition is a puzzling observation but remains to be considered as a potential tool for in-vivo marker studies of disease onset and progression. Presence of iron and calcium in thalamic plaques might be responsible for MRI detection. The origin and pathophysiological significance of such mixed aggregates will be discussed. Acknowledgments: Federation for Brain Research; Del-Duca Foundation; Neuroscience ACI research grant. Ministerio de Educacio´n, Cultura y Deporte (Spaingrant PR2002-0261. Direccio´n General de Investigacio´n (Spain): grant BMC2002-00996. We thank the Sanofi-Aventis Neurodegenerative Disease Group for the generous gift of the animals involved in this study. P2-290
IN-VIVO DETECTION OF THALAMIC AMYLOID PLAQUES BY MRI IN A LARGE POPULATION OF APP/PS1 MICE
Marc Dhenain1,2, Nadine El Tannir El Tayara2, Ting-Di Wu2, Andreas Volk2, Carmen Quintana3, Benoıˆt Delatour4, 1URA CEA-CNRS 2210, Orsay, France; 2U759 INSERM / Institut Curie, Orsay, France; 3 IMM, CSIC, Madrid, Spain; 4NAMC, CNRS UMR 8620, Orsay, France. Contact e-mail: [email protected] Background/Objectives: Thalamic plaques from transgenic mice modelling amyloidosis are more easily detected by in-vivo MRI than cortical plaques (Jack CR, Jr., MRM, 2004; Vanhoutte G, MRM, 2005). To further evaluate the characteristics of these plaques, we studied their occurrence on in-vivo/post-mortem MRI from a large population of APP/PS1 mice that were subsequently processed for neuropathological examination. Methods: In-vivo MRI exams from 32 APP/PS1 (27-103 weeks) and 36 amyloid-free PS1 (27-104 weeks) mice were recorded (T2*-weighted gradient echo sequence; TR⫽47.4ms, TE⫽20ms, Alpha⫽15°, resolution ⫽234x117x117m3, 4.7T spectrometer). In addition, post-mortem MRIs were performed on 32 APP/PS1 and 26 PS1 mice (TR⫽100ms, TE⫽20ms, alpha⫽15°, resolution⫽63x47x59m3). Brain tissues were thereafter stained for amyloid plaques, iron and calcium deposition (Congo red, PERLS-DAB, and Alizarin red stains). Results: Two categories of APP/PS1 animals were isolated on the basis of in-vivo images. Some animals (13 out of 32), displayed thalamic spots while the other ones, some of which were very old, did not display any spot. In-vivo images from only two (out of 36) PS1 mice revealed very small hypointense thalamic spots. Post-mortem MRI confirmed the occurrence of thalamic spots with greater sensitivity. For APP/PS1 mice, no linear relationship could be found between the age of the animals and the size of the spots. Registration of MR and histological sections showed that the spots detected on MRI corresponded to amyloid deposits containing dense iron-calcic aggregates. A positive correlation was noted between the size of the spots detected on postmortem images and the overall amyloid load in the thalamus. Due to lower spatial resolution, in-vivo measurements of spot sizes did not significantly correlate with regional amyloid loads. Conclusion: Thalamic plaques associated with mineralized iron-calcic aggregates can be detected by in-vivo MRI, but only in a subpopulation of APP/PS1 mice. Considering these thalamic lesions as putative surrogate markers will be discussed. Acknowledgments: “Federation for Brain Research”; Del-Duca Foundation; “Neuroscience ACI research program” (French Minister for Research). Ministerio de Educacio´n, Cultura y Deporte (Spain): grant PR2002-0261. Direccio´n General de Investigacio´n (Spain):grant BMC2002-00996. We thank the Sanofi-Aventis Neurodegenerative Disease Group for the generous gift of the animals involved in this study.
Poster P2:: Monday Posters LONGITUDINAL QUANTITATIVE MRI R2 RELAXOMETRY IN ELDERLY PARTICIPANTS REPORTING MEMORY LOSS: A USEFUL TOOL FOR THE MONITORING OF DEMENTIA ONSET?
Jonathan K. Foster1,2, Michael J. House3, Timothy G. St Pierre3, Ralph N. Martins1, Roger Clarnette4, Jodie Ricci5, 1Edith Cowan University, Joondalup, Australia; 2Neurosciences Unit, Mt Claremont, Australia; 3University of Western Australia, Crawley, Australia; 4 Department of Geriatric Medicine, Fremantle Hospital, Australia; 5 SKG Radiology, Subiaco, Australia. Contact e-mail: [email protected] Background: Magnetic resonance imaging (MRI) can be applied as a useful, non-invasive tool for characterizing, in vivo, the neurological changes associated with age-related memory loss and dementia. The transverse proton relaxation rate, R2, is an MRI parameter affected by changes in both brain iron concentration and water content. Objective(s): The objective of this pilot study was to assess longitudinal changes in R2 measured in elderly participants with mild-severe levels of cognitive impairment, and to determine the degree to which any changes in R2 signal over time were associated with changes in cognitive functioning. Methods: Six elderly participants reporting memory problems underwent two 1.5T MRI scans 12 to 24 months apart, with neuropsychological testing taking place in close temporal proximity to the scans outside the magnet. R2 data were collected from 14 brain regions in all participants. Correlations between annualized percentage changes in R2 values and annualized changes in cognitive scores were assessed. Conclusions: There were significant negative correlations between cognitive changes and R2 changes in the right temporal cortex and left hippocampus. In contrast, there were significant positive correlations between cognitive changes and R2 changes in the left temporal and parahippocampal cortex and in the right internal capsule, thalamus and putamen. These findings suggest that in vivo quantitative changes in R2 may be capable of characterizing neurological processes associated with age-related cognitive decline. Specifically, this technique may offer a useful tool for the monitoring of neurocognitive changes associated with the onset of dementia. P2-289
IN-VIVO MRI DETECTABLE THALAMIC AMYLOID-ASSOCIATED AGGREGATES DEVELOPED BY MUTATED APP/PS1 TRANSGENIC MICE: WHAT ARE THEY?
Benoıˆt Delatour1, Marc Dhenain2,3, Ting-Di Wu3, Nadine El Tannir El Tayara3, Andreas Volk3, Carmen Quintana4, 1 NAMC, CNRS UMR 8620, Orsay, France; 2URA CEA - CNRS 2210, Orsay, France; 3U759 INSERM / Institut Curie, Orsay, France; 4IMM, CSIC, Madrid, Spain. Contact e-mail: [email protected] Background/Objectives: Several transgenic mouse lines modelling Alzheimer’s brain amyloidosis were recently diagnosed with in-vivo MRI-detected localized thalamic lesions described as hypointense spots. We replicated these observations in an APP/PS1 model (Delatour et al, Neurob. Aging, 2006) and tried to assess the nature and origin of such brain alterations. Methods: Brains from transgenics with or without thalamic spots were processed for extended neuropathological examination including (immuno-)histochemical, ultrastructural (EM) and elemental (X-rays, nanoSIMS) analysis. Results: Matching MRI-detected spots topography, crystal-like aggregates were found in ventral/ posterior thalamic nuclei associated with dense peripheral microglial activation. These lesions were closely associated with amyloid plaques and, as demonstrated by complementary analysis, were characterized as mineral deposits with iron content. Levels of inflammation surrounding these thalamic aggregates did not differ from microgliosis classically observed surrounding A plaques. No sign of microhemorrhage nor abnormal vasculature were observed in APP/PS1 mice with thalamic aggregates. Lack of vascular impairment was further supported by
negative findings from in-vivo MR angiography. We finally addressed the occurrence of focal neurodegenerative processes that may be linked or explain the occurrence of localized thalamic brain lesions. Conclusion: Constancy of MRI-detected thalamic lesions in different monogenic and bigenic transgenic mice developing A brain deposition is a puzzling observation but remains to be considered as a potential tool for in-vivo marker studies of disease onset and progression. Presence of iron and calcium in thalamic plaques might be responsible for MRI detection. The origin and pathophysiological significance of such mixed aggregates will be discussed. Acknowledgments: Federation for Brain Research; Del-Duca Foundation; Neuroscience ACI research grant. Ministerio de Educacio´n, Cultura y Deporte (Spaingrant PR2002-0261. Direccio´n General de Investigacio´n (Spain): grant BMC2002-00996. We thank the Sanofi-Aventis Neurodegenerative Disease Group for the generous gift of the animals involved in this study. P2-290
IN-VIVO DETECTION OF THALAMIC AMYLOID PLAQUES BY MRI IN A LARGE POPULATION OF APP/PS1 MICE
Marc Dhenain1,2, Nadine El Tannir El Tayara2, Ting-Di Wu2, Andreas Volk2, Carmen Quintana3, Benoıˆt Delatour4, 1URA CEA-CNRS 2210, Orsay, France; 2U759 INSERM / Institut Curie, Orsay, France; 3 IMM, CSIC, Madrid, Spain; 4NAMC, CNRS UMR 8620, Orsay, France. Contact e-mail: [email protected] Background/Objectives: Thalamic plaques from transgenic mice modelling amyloidosis are more easily detected by in-vivo MRI than cortical plaques (Jack CR, Jr., MRM, 2004; Vanhoutte G, MRM, 2005). To further evaluate the characteristics of these plaques, we studied their occurrence on in-vivo/post-mortem MRI from a large population of APP/PS1 mice that were subsequently processed for neuropathological examination. Methods: In-vivo MRI exams from 32 APP/PS1 (27-103 weeks) and 36 amyloid-free PS1 (27-104 weeks) mice were recorded (T2*-weighted gradient echo sequence; TR⫽47.4ms, TE⫽20ms, Alpha⫽15°, resolution ⫽234x117x117m3, 4.7T spectrometer). In addition, post-mortem MRIs were performed on 32 APP/PS1 and 26 PS1 mice (TR⫽100ms, TE⫽20ms, alpha⫽15°, resolution⫽63x47x59m3). Brain tissues were thereafter stained for amyloid plaques, iron and calcium deposition (Congo red, PERLS-DAB, and Alizarin red stains). Results: Two categories of APP/PS1 animals were isolated on the basis of in-vivo images. Some animals (13 out of 32), displayed thalamic spots while the other ones, some of which were very old, did not display any spot. In-vivo images from only two (out of 36) PS1 mice revealed very small hypointense thalamic spots. Post-mortem MRI confirmed the occurrence of thalamic spots with greater sensitivity. For APP/PS1 mice, no linear relationship could be found between the age of the animals and the size of the spots. Registration of MR and histological sections showed that the spots detected on MRI corresponded to amyloid deposits containing dense iron-calcic aggregates. A positive correlation was noted between the size of the spots detected on postmortem images and the overall amyloid load in the thalamus. Due to lower spatial resolution, in-vivo measurements of spot sizes did not significantly correlate with regional amyloid loads. Conclusion: Thalamic plaques associated with mineralized iron-calcic aggregates can be detected by in-vivo MRI, but only in a subpopulation of APP/PS1 mice. Considering these thalamic lesions as putative surrogate markers will be discussed. Acknowledgments: “Federation for Brain Research”; Del-Duca Foundation; “Neuroscience ACI research program” (French Minister for Research). Ministerio de Educacio´n, Cultura y Deporte (Spain): grant PR2002-0261. Direccio´n General de Investigacio´n (Spain):grant BMC2002-00996. We thank the Sanofi-Aventis Neurodegenerative Disease Group for the generous gift of the animals involved in this study.