- Email: [email protected]
Diffusion tensor imaging can differentiate human Alzheimer brain from normal brain
Poster Presentations P2 system motivates olfactory functional testing to investigate AD and to contribute to detection of dementia.
P2-383
GENE EXPRESSION CORRELATES OF HIPPOCAMPAL ATROPHY ACROSS IN COGNITIVELY NORMAL ELDERLY AND MCI
Liana G. Apostolova, Kristy S. Hwang, Jason J. Lee, Fuying Gao, Paul M. Thompson, John Ringman, Jeffrey L. Cummings, Giovanni Coppola, UCLA, Los Angeles, CA, USA. Contact e-mail: lapostolova@mednet. ucla.edu Background: Human genome-wide gene expression studies have generated important knowledge about the unique influences of multiple genes in health and disease. The complex interactions between gene expression and structural changes observed in Alzheimer’s disease (AD) and the at-risk state of mild cognitive impairment (MCI) may yield important insights about genetic influences on the pathogenesis of AD. Methods: We collected peripheral blood and 3D MPRAGE T1-weighted MRI data in 40 cognitively normal (NC), 19 nonamnestic and 22 amnestic MCI subjects. Peripheral blood RNA was extracted using Paxgene tubes, amplified, labeled, and hybridized onto Illumina Human RefSeq-8 BeadChip arrays, querying the expression of w22,000 RefSeq curated transcripts followed by quality control, and quantile normalization with R and Bioconductor packages. Hippocampi were segmented with novel automated segmentation technique and further analyzed with the radial distance approach. We applied linear regression models to study the relationship between log2-transformed absolute gene expression levels and hippocampal radial distance while adjusting for age and sex. For multiple comparison correction we used permutation tests with a threshold of p < 0.01. Results: We found significant associations between hippocampal atrophy and higher expression levels for two genes that are known to play a role in degradation of misfolded proteins including Abeta - PARK2 and DNAJC12. Elevated expression of IL1RAPL2 - a gene associated with inflammatory response, as well as ALS2CR11 and HAP1 that have been linked with two other neurodegenerative disorders - amyotrophic lateral sclerosis and Huntington’s disease, respectively - likewise showed significant correlation with hippocampal atrophy. Several genes known for their role in neuronal survival, axono- and synaptogenesis - GH1, SYN1 and CNTN2 - were significantly upregulated in subjects with hippocampal atrophy. Conclusions: Our data suggests that neurodegenerative neuronal and synaptic loss leads to over-expression of genes associated with neuronal and synaptic survival in MCI. The presence of toxic misfolded proteins such as Abeta likely triggers over-expression of genes involved in the degradation of misfolded proteins through the ubiquitin-proteasome and the chaperone-endoplasmic reticulum pathways. Over-expression of genes associated with other neurodegenerative disorders suggests that some pathophysiologic events may be shared across the neurodegenerative spectrum. Peripheral blood gene expression shows promise as a biomarker for neurodegenerative disorders.
P2-384
S429 DIFFUSION TENSOR IMAGING CAN DIFFERENTIATE HUMAN ALZHEIMER BRAIN FROM NORMAL BRAIN
Palamadai N. Venkatasubramanian1,2, Eileen H. Bigio3, Jason C. Pych1,2, Sandra Weintraub3, Marsel -M Mesulam3, Alice M. Wyrwicz1,2, 1NorthShore University HealthSystem Research Institute, Evanston, IL, USA; 2 Pritzker School of Medicine, University of Chicago, Chicago, IL, USA; 3 Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Contact e-mail: [email protected] Background: Disruption of hippocampal circuit that leads to memory dysfunction may involve neuroanatomical changes to specific regions of the circuit. Diffusion tensor MR imaging (DTI) can be used to investigate these alterations since water diffusion in the brain tissue is strongly influenced by cellular organization and neuronal architecture. Fractional anisotropy (FA) and diffusivity, measured by DTI would be suitable imaging correlates of the neuroanatomical changes that occur in the hippocampus and related structures. Using ex vivo DTI, we have examined brain samples from cognitively normal subjects, MCI patients and AD patients and found differences between them in FA, diffusivity and directionality of water diffusion. Methods: Brain samples were obtained from Northwestern University AD Center. High spatial resolution DTI images of brain tissue were acquired on a 14.1T microimager from which FA, diffusivity and directionality were calculated for each pixel and averaged for regions of interest comprising structures in the hippocampal circuit. Results: Entorhinal cortex, dentate gyrus, CA1 subfield of the hippocampus and perforant path showed a decrease in FA in the AD brain compared to the normal brain, but by varying degrees. The largest decrease in FA of w30% was seen in the perforant path. As expected, decreased directionality and increased diffusivity were associated with this decrease in anisotropy. FA in the dentate gyrus of the AD brain was w24% lower than that in the normal brain with a corresponding increase in diffusivity. The decreases in FA measured in AD brain CA1 and entorhinal cortex were much smaller, only w10%. The observed changes in diffusion characteristics in the AD brain suggest a decrease in cellular organization in entorhinal cortex, dentate gyrus, CA1 subfield and perforant path as a result of AD neuropathology. The hippocampal region of the MCI brains also exhibited a similar pattern of difference from normal human brains. Differences between MCI brains and AD brains were not remarkable. Conclusions: From our results it is clear that some regions of the hippocampal circuit are more vulnerable to AD than others. Measurement of diffusion anisotropy using high spatial resolution DTI may have potential in understanding the pathophysiology of AD progression.
P2-385
BINDING AND PHARMACOKINETIC PROPERTIES OF NOVEL 18F-LABELED AGENTS FOR IN VIVO IMAGING OF TAU PATHOLOGY IN ALZHEIMER’S DISEASE
Nobuyuki Okamura1, Shozo Furumoto1, Katsutoshi Furukawa2, Hiroyuki Arai2, Kazuhiko Yanai1, Yukitsuka Kudo3, 1Tohoku University School of Medicine, Sendai, Japan; 2Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan; 3Innovation of New Biomedical Engineering Center, Tohoku University, Sendai, Japan. Contact e-mail: oka@ mail.tains.tohoku.ac.jp Background: The deposition of senile plaques and neurofibrillary tangles represents a pathological hallmark of Alzheimer’s disease (AD). Individual evaluation of the distributions of senile plaques and neurofibrillary tangles is desirable to obtain a better understanding of the pathophysiology of AD. However, no surrogate markers exist that allow evaluation of the severity of tau pathology in AD brains. To develop novel PET imaging agents with high binding specificity for neurofibrillary tangles, we evaluated the profiles of novel 18F-labeled compounds (Cpd.B and C) as candidate tau-imaging probes. Methods: Binding selectivity of test compounds for senile plaques and neurofibrillary tangles was evaluated by fluorescence microscopy and
P2-383
GENE EXPRESSION CORRELATES OF HIPPOCAMPAL ATROPHY ACROSS IN COGNITIVELY NORMAL ELDERLY AND MCI
Liana G. Apostolova, Kristy S. Hwang, Jason J. Lee, Fuying Gao, Paul M. Thompson, John Ringman, Jeffrey L. Cummings, Giovanni Coppola, UCLA, Los Angeles, CA, USA. Contact e-mail: lapostolova@mednet. ucla.edu Background: Human genome-wide gene expression studies have generated important knowledge about the unique influences of multiple genes in health and disease. The complex interactions between gene expression and structural changes observed in Alzheimer’s disease (AD) and the at-risk state of mild cognitive impairment (MCI) may yield important insights about genetic influences on the pathogenesis of AD. Methods: We collected peripheral blood and 3D MPRAGE T1-weighted MRI data in 40 cognitively normal (NC), 19 nonamnestic and 22 amnestic MCI subjects. Peripheral blood RNA was extracted using Paxgene tubes, amplified, labeled, and hybridized onto Illumina Human RefSeq-8 BeadChip arrays, querying the expression of w22,000 RefSeq curated transcripts followed by quality control, and quantile normalization with R and Bioconductor packages. Hippocampi were segmented with novel automated segmentation technique and further analyzed with the radial distance approach. We applied linear regression models to study the relationship between log2-transformed absolute gene expression levels and hippocampal radial distance while adjusting for age and sex. For multiple comparison correction we used permutation tests with a threshold of p < 0.01. Results: We found significant associations between hippocampal atrophy and higher expression levels for two genes that are known to play a role in degradation of misfolded proteins including Abeta - PARK2 and DNAJC12. Elevated expression of IL1RAPL2 - a gene associated with inflammatory response, as well as ALS2CR11 and HAP1 that have been linked with two other neurodegenerative disorders - amyotrophic lateral sclerosis and Huntington’s disease, respectively - likewise showed significant correlation with hippocampal atrophy. Several genes known for their role in neuronal survival, axono- and synaptogenesis - GH1, SYN1 and CNTN2 - were significantly upregulated in subjects with hippocampal atrophy. Conclusions: Our data suggests that neurodegenerative neuronal and synaptic loss leads to over-expression of genes associated with neuronal and synaptic survival in MCI. The presence of toxic misfolded proteins such as Abeta likely triggers over-expression of genes involved in the degradation of misfolded proteins through the ubiquitin-proteasome and the chaperone-endoplasmic reticulum pathways. Over-expression of genes associated with other neurodegenerative disorders suggests that some pathophysiologic events may be shared across the neurodegenerative spectrum. Peripheral blood gene expression shows promise as a biomarker for neurodegenerative disorders.
P2-384
S429 DIFFUSION TENSOR IMAGING CAN DIFFERENTIATE HUMAN ALZHEIMER BRAIN FROM NORMAL BRAIN
Palamadai N. Venkatasubramanian1,2, Eileen H. Bigio3, Jason C. Pych1,2, Sandra Weintraub3, Marsel -M Mesulam3, Alice M. Wyrwicz1,2, 1NorthShore University HealthSystem Research Institute, Evanston, IL, USA; 2 Pritzker School of Medicine, University of Chicago, Chicago, IL, USA; 3 Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Contact e-mail: [email protected] Background: Disruption of hippocampal circuit that leads to memory dysfunction may involve neuroanatomical changes to specific regions of the circuit. Diffusion tensor MR imaging (DTI) can be used to investigate these alterations since water diffusion in the brain tissue is strongly influenced by cellular organization and neuronal architecture. Fractional anisotropy (FA) and diffusivity, measured by DTI would be suitable imaging correlates of the neuroanatomical changes that occur in the hippocampus and related structures. Using ex vivo DTI, we have examined brain samples from cognitively normal subjects, MCI patients and AD patients and found differences between them in FA, diffusivity and directionality of water diffusion. Methods: Brain samples were obtained from Northwestern University AD Center. High spatial resolution DTI images of brain tissue were acquired on a 14.1T microimager from which FA, diffusivity and directionality were calculated for each pixel and averaged for regions of interest comprising structures in the hippocampal circuit. Results: Entorhinal cortex, dentate gyrus, CA1 subfield of the hippocampus and perforant path showed a decrease in FA in the AD brain compared to the normal brain, but by varying degrees. The largest decrease in FA of w30% was seen in the perforant path. As expected, decreased directionality and increased diffusivity were associated with this decrease in anisotropy. FA in the dentate gyrus of the AD brain was w24% lower than that in the normal brain with a corresponding increase in diffusivity. The decreases in FA measured in AD brain CA1 and entorhinal cortex were much smaller, only w10%. The observed changes in diffusion characteristics in the AD brain suggest a decrease in cellular organization in entorhinal cortex, dentate gyrus, CA1 subfield and perforant path as a result of AD neuropathology. The hippocampal region of the MCI brains also exhibited a similar pattern of difference from normal human brains. Differences between MCI brains and AD brains were not remarkable. Conclusions: From our results it is clear that some regions of the hippocampal circuit are more vulnerable to AD than others. Measurement of diffusion anisotropy using high spatial resolution DTI may have potential in understanding the pathophysiology of AD progression.
P2-385
BINDING AND PHARMACOKINETIC PROPERTIES OF NOVEL 18F-LABELED AGENTS FOR IN VIVO IMAGING OF TAU PATHOLOGY IN ALZHEIMER’S DISEASE
Nobuyuki Okamura1, Shozo Furumoto1, Katsutoshi Furukawa2, Hiroyuki Arai2, Kazuhiko Yanai1, Yukitsuka Kudo3, 1Tohoku University School of Medicine, Sendai, Japan; 2Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan; 3Innovation of New Biomedical Engineering Center, Tohoku University, Sendai, Japan. Contact e-mail: oka@ mail.tains.tohoku.ac.jp Background: The deposition of senile plaques and neurofibrillary tangles represents a pathological hallmark of Alzheimer’s disease (AD). Individual evaluation of the distributions of senile plaques and neurofibrillary tangles is desirable to obtain a better understanding of the pathophysiology of AD. However, no surrogate markers exist that allow evaluation of the severity of tau pathology in AD brains. To develop novel PET imaging agents with high binding specificity for neurofibrillary tangles, we evaluated the profiles of novel 18F-labeled compounds (Cpd.B and C) as candidate tau-imaging probes. Methods: Binding selectivity of test compounds for senile plaques and neurofibrillary tangles was evaluated by fluorescence microscopy and