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Resting bold fMRI differentiates dementia with Lewy bodies vs. Alzheimer's disease
Additional Abstracts P4-450
A NEW THERAPEUTIC STRATEGY AGAINST ALZHEIMER’S DISEASE (AD) AND OTHER BRAIN DISEASES: INTRACELLULAR NEUROTRANSPORT DELIVERY (I.NT.) OF CBNGF AND CB-CARGO CONJUGATES MAY RESCUE AD AND OTHER BRAIN DISEASES
Xuancai Wan, Peking Union Med College (PUMC)/Chinese Academy of Med Sciences(CAMS), Beijing, China. Background: The blood-brain barrier (BBB) excludes neurotrophic factors and/or other therapeutic proteins with large molecular weight from the brain parenchyma, so that these potential drugs against Alzheimer’s disease(AD) cannot be used with any non-invasive measures by clinicians or patients themselves. The well-known central effect of the nerve growth factor (NGF) is that it rescues cholinergic neurons in the basal forebrain from toxicity or trauma. Although the first neurotrophin NGF won the Nobel prize for medicine and physiology in 1986, and is widely used in basic research with invasive measures, but still sleeping outside the clinical field of brain diseases. Methods: CB-NGF and CB-cargo were prepared according our lab’s modifications of di-sulfide (S-S) method or NaIO4 method. Hippocampus destroyed rats and/or beta-Amyloid peptide 25-35 - induced amnesic mice were used as AD-like models. Expts in vitro were performed in PC12 cell culture conditioning with CB-NGF, native NGF and CB. Western blotting tests of NGF and CB-NGF receptor combining on TrkA and pTrkA (post binding phosphorylation of TrkA) were also performed with PC12 cells. Morris water maze (MWM) tests were performed in AD-like models. Results: Both conjugation procedures(S-S and/or NaIO4) have no influence on the bioactivity of CB and its cargos. The time windows in Western blotting of NGF and CB-NGF on pTrkA binding were different, the CB-NGF-pTrkA combining time was postponed almost 30 min later than NGF-pTrkA , it indicates the TrkA non-combined CB-NGF has been occupied the GM1 binding site and internalized in the first period, or GM1-CB-NGF combining is more powerful than NGF-TrkA’s and can push the CB-NGF-pTrkA binding to a later phase, this makes the TrkA non-combined CB-NGF possessing a secondary NGF transneuronal effects in vivo. In both rat and mouse AD model MWM tests showed in the CB-NGF treated group, the spatial learning and memory were significantly improved with comparison of the NGF administered ones. The ChAT positive neurons in the nucleus basalis of Meynert and diagonal band of Broca were almost fully rescued in CB-NGF treated AD models. Furthermore, the stem cell/progenitor stream in the forebrain of the CB-NGF treated mice was significantly enhanced in the core of the olfactory bulb (BrdU labeled cell counting). All these transneuronal effects indicate that CB-NGF nasally administered may rescue AD via i.nt. (partly published in Neuroscience 2008, 155:234) Conclusions: CB-cargo targeting i.nt. provides a proof-of-principle milestone in the therapeutic approach of neurodegenerative brain diseases with CB conjugated macromolecular weight polypeptides or immunoglobulins etc. With its specific powerful GM1-CB neurotransport and secondary transneuronal effects, CB-cargo provides a novel route of entrance into the brain parenchyma and a new therapeutic strategy bypassing BBB for targeting into the CNS. These stably covalent new compounds (CB-NGF etc) are deserved as a patent for industrialization.
P4-452
RESTING BOLD fMRI DIFFERENTIATES DEMENTIA WITH LEWY BODIES VS. ALZHEIMER’S DISEASE
James Galvin1, Joseph Price2, Zhizi Yan2, John Morris2, Yvette Sheline2, 1 New York University Langone Medical Center, New York, New York, United States; 2Washington University, St Louis, Missouri, United States. Background: Clinicopathological phenotypes of Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) often overlap, making discrimination difficult. We performed resting state Blood Oxygen Level
e69
Dependent (BOLD) functional connectivity MRI (fcMRI) to determine whether there were differences between AD and DLB. Methods: Participants (n ¼ 88) enrolled in a longitudinal study of memory and aging underwent 3T fcMRI. Clinical diagnoses of probable DLB (n ¼ 15) were made according to published criteria. Cognitively normal control participant (n ¼ 38) were selected for the absence of cerebral amyloid burden as imaged with Pittsburgh Compound B (PIB). Probable AD cases (n ¼ 35) met published criteria and had appreciable amyloid deposits with PIB imaging. Functional images were collected using a gradient spinecho sequence sensitive to BOLD contrast (T2*-weighting). Correlation maps selected a seed region in the combined bilateral precuneus. Results: DLB participants had a functional connectivity pattern for the precuneus seed region that was distinct from AD; both the DLB and AD groups had functional connectivity patterns that differed from the cognitively normal group. We found increased connectivity between the precuneus and regions in the dorsal attention network and the putamen. In contrast, we found decreased connectivity between the precuneus and other task-negative default regions and visual cortices. There was also a reversal of connectivity in the right hippocampus. Conclusions: The changes in functional connectivity in DLB described here suggest distinct patterns of activation that may assist in discrimination of DLB from AD and cognitively normal participants. In studies of individuals with symptomatic AD and cognitively intact controls, the use of BOLD fcMRI may identify "preclinical" disease in individuals without apparent cognitive abnormalities. Since patterns of connectivity differ between AD and DLB groups, measurements of BOLD functional connectivity potentially can shed further light on neuroanatomic connections that distinguish DLB from AD. Using alteration in DMN functional connectivity, we may be able to improve our understanding of the pathophysiology of different dementia etiologies such as AD and DLB.
P4-453
GENOME-WIDE ASSOCIATION ANALYSIS USING CEREBROSPINAL FLUID ABETA42 LEVELS AS AN ENDOPHENOTYPE FOR ALZHEIMER’S DISEASE
John Kauwe1, Carlos Cruchaga2, David McKean1, Matthew Bailey1, David Patty1, Kevin Mayo3, Sarah Bertelsen3, Anthony Hinrichs3, The Alzheimer’s Disease Genetics Consortium, The Alzheimer’s Disease Neuroimaging Initiative, Anne Fagan2, David Holtzman3, Alison Goate3, 1 Brigham Young University, Provo, Utah, United States; 2Washington University School of Medicine, St Louis, Missouri, United States; 3 Washington University, St Louis, Missouri, United States. Background: Cerebrospinal fluid (CSF) Aß42, and tau are promising biomarkers for Alzheimer’s Disease (AD). Using candidate gene based approaches we have identified several genetic factors associated with CSF Aß42 and risk for AD. Here we have performed a genome-wide association study using CSF Aß42 levels as endophenotypes to identify additional genetic factors implicated on AD. Methods: Measurements of CSF Aß42 levels were obtained in 957 samples including 356 samples from the Knight Alzheimer’s Disease Research Center at Washington University, 391 from the Alzheimer’s Disease Neuroimaging Initiative and 210 came from the University of Washington. Analyses were restricted to individuals with European American ancestry. Approximately 275,000 SNPs were directly genotyped in all series using Illumina BeadChips. As CSF Aß42 levels are not normally distributed and absolute levels of the measurements differed between samples we analyzed each series separately. Series specific analyses were performed using linear regression with age, principle components from stratification analyses and/or APOE genotype as covariates. Empirical P-values for each SNP were generated using ten million permutations. All association analyses were performed using PLINK. Meta analysis of the three series incorporating sample size and effect direction was performed using METAL. Results: Two SNPs in the APOE-TOMM40 gene region showed genome-wide
A NEW THERAPEUTIC STRATEGY AGAINST ALZHEIMER’S DISEASE (AD) AND OTHER BRAIN DISEASES: INTRACELLULAR NEUROTRANSPORT DELIVERY (I.NT.) OF CBNGF AND CB-CARGO CONJUGATES MAY RESCUE AD AND OTHER BRAIN DISEASES
Xuancai Wan, Peking Union Med College (PUMC)/Chinese Academy of Med Sciences(CAMS), Beijing, China. Background: The blood-brain barrier (BBB) excludes neurotrophic factors and/or other therapeutic proteins with large molecular weight from the brain parenchyma, so that these potential drugs against Alzheimer’s disease(AD) cannot be used with any non-invasive measures by clinicians or patients themselves. The well-known central effect of the nerve growth factor (NGF) is that it rescues cholinergic neurons in the basal forebrain from toxicity or trauma. Although the first neurotrophin NGF won the Nobel prize for medicine and physiology in 1986, and is widely used in basic research with invasive measures, but still sleeping outside the clinical field of brain diseases. Methods: CB-NGF and CB-cargo were prepared according our lab’s modifications of di-sulfide (S-S) method or NaIO4 method. Hippocampus destroyed rats and/or beta-Amyloid peptide 25-35 - induced amnesic mice were used as AD-like models. Expts in vitro were performed in PC12 cell culture conditioning with CB-NGF, native NGF and CB. Western blotting tests of NGF and CB-NGF receptor combining on TrkA and pTrkA (post binding phosphorylation of TrkA) were also performed with PC12 cells. Morris water maze (MWM) tests were performed in AD-like models. Results: Both conjugation procedures(S-S and/or NaIO4) have no influence on the bioactivity of CB and its cargos. The time windows in Western blotting of NGF and CB-NGF on pTrkA binding were different, the CB-NGF-pTrkA combining time was postponed almost 30 min later than NGF-pTrkA , it indicates the TrkA non-combined CB-NGF has been occupied the GM1 binding site and internalized in the first period, or GM1-CB-NGF combining is more powerful than NGF-TrkA’s and can push the CB-NGF-pTrkA binding to a later phase, this makes the TrkA non-combined CB-NGF possessing a secondary NGF transneuronal effects in vivo. In both rat and mouse AD model MWM tests showed in the CB-NGF treated group, the spatial learning and memory were significantly improved with comparison of the NGF administered ones. The ChAT positive neurons in the nucleus basalis of Meynert and diagonal band of Broca were almost fully rescued in CB-NGF treated AD models. Furthermore, the stem cell/progenitor stream in the forebrain of the CB-NGF treated mice was significantly enhanced in the core of the olfactory bulb (BrdU labeled cell counting). All these transneuronal effects indicate that CB-NGF nasally administered may rescue AD via i.nt. (partly published in Neuroscience 2008, 155:234) Conclusions: CB-cargo targeting i.nt. provides a proof-of-principle milestone in the therapeutic approach of neurodegenerative brain diseases with CB conjugated macromolecular weight polypeptides or immunoglobulins etc. With its specific powerful GM1-CB neurotransport and secondary transneuronal effects, CB-cargo provides a novel route of entrance into the brain parenchyma and a new therapeutic strategy bypassing BBB for targeting into the CNS. These stably covalent new compounds (CB-NGF etc) are deserved as a patent for industrialization.
P4-452
RESTING BOLD fMRI DIFFERENTIATES DEMENTIA WITH LEWY BODIES VS. ALZHEIMER’S DISEASE
James Galvin1, Joseph Price2, Zhizi Yan2, John Morris2, Yvette Sheline2, 1 New York University Langone Medical Center, New York, New York, United States; 2Washington University, St Louis, Missouri, United States. Background: Clinicopathological phenotypes of Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) often overlap, making discrimination difficult. We performed resting state Blood Oxygen Level
e69
Dependent (BOLD) functional connectivity MRI (fcMRI) to determine whether there were differences between AD and DLB. Methods: Participants (n ¼ 88) enrolled in a longitudinal study of memory and aging underwent 3T fcMRI. Clinical diagnoses of probable DLB (n ¼ 15) were made according to published criteria. Cognitively normal control participant (n ¼ 38) were selected for the absence of cerebral amyloid burden as imaged with Pittsburgh Compound B (PIB). Probable AD cases (n ¼ 35) met published criteria and had appreciable amyloid deposits with PIB imaging. Functional images were collected using a gradient spinecho sequence sensitive to BOLD contrast (T2*-weighting). Correlation maps selected a seed region in the combined bilateral precuneus. Results: DLB participants had a functional connectivity pattern for the precuneus seed region that was distinct from AD; both the DLB and AD groups had functional connectivity patterns that differed from the cognitively normal group. We found increased connectivity between the precuneus and regions in the dorsal attention network and the putamen. In contrast, we found decreased connectivity between the precuneus and other task-negative default regions and visual cortices. There was also a reversal of connectivity in the right hippocampus. Conclusions: The changes in functional connectivity in DLB described here suggest distinct patterns of activation that may assist in discrimination of DLB from AD and cognitively normal participants. In studies of individuals with symptomatic AD and cognitively intact controls, the use of BOLD fcMRI may identify "preclinical" disease in individuals without apparent cognitive abnormalities. Since patterns of connectivity differ between AD and DLB groups, measurements of BOLD functional connectivity potentially can shed further light on neuroanatomic connections that distinguish DLB from AD. Using alteration in DMN functional connectivity, we may be able to improve our understanding of the pathophysiology of different dementia etiologies such as AD and DLB.
P4-453
GENOME-WIDE ASSOCIATION ANALYSIS USING CEREBROSPINAL FLUID ABETA42 LEVELS AS AN ENDOPHENOTYPE FOR ALZHEIMER’S DISEASE
John Kauwe1, Carlos Cruchaga2, David McKean1, Matthew Bailey1, David Patty1, Kevin Mayo3, Sarah Bertelsen3, Anthony Hinrichs3, The Alzheimer’s Disease Genetics Consortium, The Alzheimer’s Disease Neuroimaging Initiative, Anne Fagan2, David Holtzman3, Alison Goate3, 1 Brigham Young University, Provo, Utah, United States; 2Washington University School of Medicine, St Louis, Missouri, United States; 3 Washington University, St Louis, Missouri, United States. Background: Cerebrospinal fluid (CSF) Aß42, and tau are promising biomarkers for Alzheimer’s Disease (AD). Using candidate gene based approaches we have identified several genetic factors associated with CSF Aß42 and risk for AD. Here we have performed a genome-wide association study using CSF Aß42 levels as endophenotypes to identify additional genetic factors implicated on AD. Methods: Measurements of CSF Aß42 levels were obtained in 957 samples including 356 samples from the Knight Alzheimer’s Disease Research Center at Washington University, 391 from the Alzheimer’s Disease Neuroimaging Initiative and 210 came from the University of Washington. Analyses were restricted to individuals with European American ancestry. Approximately 275,000 SNPs were directly genotyped in all series using Illumina BeadChips. As CSF Aß42 levels are not normally distributed and absolute levels of the measurements differed between samples we analyzed each series separately. Series specific analyses were performed using linear regression with age, principle components from stratification analyses and/or APOE genotype as covariates. Empirical P-values for each SNP were generated using ten million permutations. All association analyses were performed using PLINK. Meta analysis of the three series incorporating sample size and effect direction was performed using METAL. Results: Two SNPs in the APOE-TOMM40 gene region showed genome-wide