- Email: [email protected]
EFFECT OF VITAMIN B12 ON COGNITION
Poster Presentations: Tuesday, July 26, 2016
Western blotting, and the level of neurotoxicity measured in a livedead cell assay using mouse primary hippocampal culture. Ab40/42 solutions were treated with a series of phenol-triazoles in order to monitor aggregation changes by fluorescence using K114. Results: Ab40/42SEC isolates demonstrated unique spectral shifts when incubated with K114. Oligomeric Ab aggregates were more toxic in comparison to Ab fibrillar species. A series of phenol-triazole derivatives inhibit the formation of oligomers by promoting the formation of high molecular weight aggregates, suggesting they can regulate Ab-associated neurotoxicity, which can be monitored in real time by spectral fluorescence changes using functional probes. In a live-dead cell assay, several phenol-triazole derivatives demonstrated neuroprotective effects in mouse primary hippocampal culture. Conclusions: Our novel spectral analysis is capable of detecting differences in fluorescence intensity and spectral shifts in the presence of Ab40/42 oligomers or fibrils. A series of phenol-triazoles promotes less toxic high molecular weight aggregates, which can be monitored by K114 fluorescence. P3-179
DEVELOPMENT OF AN INDICATOR CELL ASSAY FOR BLOOD-BASED DIAGNOSIS OF ALZHEIMER’S DISEASE
Jennifer Joy Smith1, Samuel A. Danziger2, Leslie Miller3, Karanbir Singh3, Elaine R. Peskind4,5, Gail Li4,5, Robert Lipshutz1, John Aitchison2,3, 1PreCyte Inc, Seattle, WA, USA; 2Center for Infectious Disease Research, Seattle, WA, USA; 3Institute for Systems Biology, Seattle, WA, USA; 4VA Puget Sound Health Care System, Seattle, WA, USA; 5 University of Washington, Seattle, WA, USA. Contact e-mail: jennifer@ precyte.net Background: We have developed the Indicator Cell Assay
PlatformÔ (iCAPÔ), a broadly applicable tool for blood-based diagnostics that uses cultured cells as biosensors, capitalizing on their innate ability to integrate and respond to weak, multicomponent signals in noisy environments. To develop an assay, standardized indicator cells are exposed in vitro to serum from normal or diseased subjects and their global differential response patterns are used to train a reliable, cost-effective disease classifier based on a small number of features. In a feasibility study with 50 serum samples, the iCAP detected pre-symptomatic disease in a murine model of amyotrophic lateral sclerosis (ALS) with 94% accuracy (p-Value¼3.81E-6) and correctly identified 95% of samples from Huntington’s disease mice as non-carriers of ALS (p-Value¼2.09E-50). Methods: We initiated development of a preliminary iCAP for early detection of Alzheimer’s disease (AD). We analyzed plasma samples from diseased patients with preclinical or early symptomatic stage AD (N¼38), and normal healthy controls (N¼20). Classes were defined based on CDR scores and CSF Abeta-42 levels. Indicator cells for this experiment were neurons derived from induced pluripotent stem cells (iPSCs) (from Cellular Dynamics International (CDI)). Global cellular responses to plasma were used to generate AD classifiers using support vector machine-based disease classification. Results: The iCAP detected early-stage AD with 72% cross-validated accuracy (p-Value¼3.10E-3). iCAP features were enriched for disease-related genes, supporting the assay’s relevance for disease research. Conclusions: This work establishes a paradigm for capitalizing on the natural ability of cultured cells to detect and respond to weak disease signatures for early detection of AD from blood. As the iCAP yields multicomponent disease signatures, it has potential applications for diagnosis and disease tracking of AD with utility for clinical diagnostics and drug development.
P3-180
P889
EFFECT OF VITAMIN B12 ON COGNITION
Wonwoo Lee, Jae Jung Lee, Phil Hyu Lee, Young H. Sohn, Byoung Seok Ye, Yonsei University College of Medicine, Seoul, South Korea. Contact e-mail: [email protected] Background: The effect of serum vitamin B12 on cognitive decline is controversial. Methods: From the database of Alzheimer’s Disease Neuroimaging Initiative, 274 subjects with baseline diagnosis of normal cognition (NC), 604 patients with MCI, and 199 patients with dementia were identified. Serum vitamin B12 and CSF Alzheimer’s disease (AD) biomarkers were checked at the baseline evaluation, and subjects were categorized into higher, middle, and lower tertile group according to the baseline vitamin B12 level. Cognitive function was evaluated with Mini-Mental Status Examination (MMSE). The effects of serum vitamin B12 on longitudinal cognitive decline was evaluated with linear mixed effect model controlling for possible confounders. Results: Demographic features and baseline CSF biomarkers were comparable between the three vitamin B12 tertile groups. In NC and MCI, baseline MMSE score was higher in the higher tertile group compared to the middle and the lower tertile groups. Linear mixed effect models showed that the higher tertile group showed faster MMSE decline compared to the middle and the lower tertile groups in patients with baseline diagnosis of MCI. This effect of vitamin B12 was more prominent in male patients compared to female patients. There was no significant effect of vitamin B12 on longitudinal cognitive decline in subjects with baseline NC and dementia diagnosis. Conclusions: Higher vitamin B12 level is associated with higher baseline MMSE score and faster cognitive decline in MCI patients. Higher vitamin B12 level could be a cognitive reserve factor in MCI patients.
P3-181
EVALUATING THE RELATIONSHIP BETWEEN MARKERS OF OXIDATIVE STRESS AND COGNITIVE PERFORMANCE IN CORONARY ARTERY DISEASE PATIENTS
Alexander Adibfar1,2,3,4, Nathan Herrmann1,2,3,4, Graham Mazereeuw1,2,3, Ana C. Andreazza3, Paul I. Oh2,5, Krista L. Lanctot1,2,3,4,5, Neuropsychopharmacology Research Group4, 1Sunnybrook Research Institute, Toronto, ON, Canada; 2Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 3University of Toronto, Toronto, ON, Canada; 4 Neuropsychopharmacology Research Group, Toronto, ON, Canada; 5 University Health Network Toronto Rehabilitation Institute, Toronto, ON, Canada. Contact e-mail: [email protected] Background: Early cognitive deficits are highly prevalent and associated with increased risk for progression to dementia in patients with coronary artery disease (CAD). Oxidative stress, particularly lipid peroxidation, represents an emerging mechanism implicated in both neurodegenerative and cardiovascular diseases, but its relationship with cognitive decline has yet to be examined in CAD. The objective of the present study was to determine the association between lipid peroxidation and cognitive performance in CAD patients. Methods: Cognitive performance was measured with a standardized battery of cognitive tests: verbal memory was assessed using the California Verbal Learning Test, 2nd Ed; visuospatial memory using the Brief Visuospatial Memory TestRevised; speed of processing using the Trails Making Test A and the Digit Symbol-Coding subtest of the Weschsler Adult Intelligence Scale; and executive function using the Trails Making Test B and the FAS Verbal Fluency test. Standardized Z-scores of related tests were summed to reflect performance in cognitive domains. Lipid hydroperoxides (LPH), early-stage products of
Western blotting, and the level of neurotoxicity measured in a livedead cell assay using mouse primary hippocampal culture. Ab40/42 solutions were treated with a series of phenol-triazoles in order to monitor aggregation changes by fluorescence using K114. Results: Ab40/42SEC isolates demonstrated unique spectral shifts when incubated with K114. Oligomeric Ab aggregates were more toxic in comparison to Ab fibrillar species. A series of phenol-triazole derivatives inhibit the formation of oligomers by promoting the formation of high molecular weight aggregates, suggesting they can regulate Ab-associated neurotoxicity, which can be monitored in real time by spectral fluorescence changes using functional probes. In a live-dead cell assay, several phenol-triazole derivatives demonstrated neuroprotective effects in mouse primary hippocampal culture. Conclusions: Our novel spectral analysis is capable of detecting differences in fluorescence intensity and spectral shifts in the presence of Ab40/42 oligomers or fibrils. A series of phenol-triazoles promotes less toxic high molecular weight aggregates, which can be monitored by K114 fluorescence. P3-179
DEVELOPMENT OF AN INDICATOR CELL ASSAY FOR BLOOD-BASED DIAGNOSIS OF ALZHEIMER’S DISEASE
Jennifer Joy Smith1, Samuel A. Danziger2, Leslie Miller3, Karanbir Singh3, Elaine R. Peskind4,5, Gail Li4,5, Robert Lipshutz1, John Aitchison2,3, 1PreCyte Inc, Seattle, WA, USA; 2Center for Infectious Disease Research, Seattle, WA, USA; 3Institute for Systems Biology, Seattle, WA, USA; 4VA Puget Sound Health Care System, Seattle, WA, USA; 5 University of Washington, Seattle, WA, USA. Contact e-mail: jennifer@ precyte.net Background: We have developed the Indicator Cell Assay
PlatformÔ (iCAPÔ), a broadly applicable tool for blood-based diagnostics that uses cultured cells as biosensors, capitalizing on their innate ability to integrate and respond to weak, multicomponent signals in noisy environments. To develop an assay, standardized indicator cells are exposed in vitro to serum from normal or diseased subjects and their global differential response patterns are used to train a reliable, cost-effective disease classifier based on a small number of features. In a feasibility study with 50 serum samples, the iCAP detected pre-symptomatic disease in a murine model of amyotrophic lateral sclerosis (ALS) with 94% accuracy (p-Value¼3.81E-6) and correctly identified 95% of samples from Huntington’s disease mice as non-carriers of ALS (p-Value¼2.09E-50). Methods: We initiated development of a preliminary iCAP for early detection of Alzheimer’s disease (AD). We analyzed plasma samples from diseased patients with preclinical or early symptomatic stage AD (N¼38), and normal healthy controls (N¼20). Classes were defined based on CDR scores and CSF Abeta-42 levels. Indicator cells for this experiment were neurons derived from induced pluripotent stem cells (iPSCs) (from Cellular Dynamics International (CDI)). Global cellular responses to plasma were used to generate AD classifiers using support vector machine-based disease classification. Results: The iCAP detected early-stage AD with 72% cross-validated accuracy (p-Value¼3.10E-3). iCAP features were enriched for disease-related genes, supporting the assay’s relevance for disease research. Conclusions: This work establishes a paradigm for capitalizing on the natural ability of cultured cells to detect and respond to weak disease signatures for early detection of AD from blood. As the iCAP yields multicomponent disease signatures, it has potential applications for diagnosis and disease tracking of AD with utility for clinical diagnostics and drug development.
P3-180
P889
EFFECT OF VITAMIN B12 ON COGNITION
Wonwoo Lee, Jae Jung Lee, Phil Hyu Lee, Young H. Sohn, Byoung Seok Ye, Yonsei University College of Medicine, Seoul, South Korea. Contact e-mail: [email protected] Background: The effect of serum vitamin B12 on cognitive decline is controversial. Methods: From the database of Alzheimer’s Disease Neuroimaging Initiative, 274 subjects with baseline diagnosis of normal cognition (NC), 604 patients with MCI, and 199 patients with dementia were identified. Serum vitamin B12 and CSF Alzheimer’s disease (AD) biomarkers were checked at the baseline evaluation, and subjects were categorized into higher, middle, and lower tertile group according to the baseline vitamin B12 level. Cognitive function was evaluated with Mini-Mental Status Examination (MMSE). The effects of serum vitamin B12 on longitudinal cognitive decline was evaluated with linear mixed effect model controlling for possible confounders. Results: Demographic features and baseline CSF biomarkers were comparable between the three vitamin B12 tertile groups. In NC and MCI, baseline MMSE score was higher in the higher tertile group compared to the middle and the lower tertile groups. Linear mixed effect models showed that the higher tertile group showed faster MMSE decline compared to the middle and the lower tertile groups in patients with baseline diagnosis of MCI. This effect of vitamin B12 was more prominent in male patients compared to female patients. There was no significant effect of vitamin B12 on longitudinal cognitive decline in subjects with baseline NC and dementia diagnosis. Conclusions: Higher vitamin B12 level is associated with higher baseline MMSE score and faster cognitive decline in MCI patients. Higher vitamin B12 level could be a cognitive reserve factor in MCI patients.
P3-181
EVALUATING THE RELATIONSHIP BETWEEN MARKERS OF OXIDATIVE STRESS AND COGNITIVE PERFORMANCE IN CORONARY ARTERY DISEASE PATIENTS
Alexander Adibfar1,2,3,4, Nathan Herrmann1,2,3,4, Graham Mazereeuw1,2,3, Ana C. Andreazza3, Paul I. Oh2,5, Krista L. Lanctot1,2,3,4,5, Neuropsychopharmacology Research Group4, 1Sunnybrook Research Institute, Toronto, ON, Canada; 2Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 3University of Toronto, Toronto, ON, Canada; 4 Neuropsychopharmacology Research Group, Toronto, ON, Canada; 5 University Health Network Toronto Rehabilitation Institute, Toronto, ON, Canada. Contact e-mail: [email protected] Background: Early cognitive deficits are highly prevalent and associated with increased risk for progression to dementia in patients with coronary artery disease (CAD). Oxidative stress, particularly lipid peroxidation, represents an emerging mechanism implicated in both neurodegenerative and cardiovascular diseases, but its relationship with cognitive decline has yet to be examined in CAD. The objective of the present study was to determine the association between lipid peroxidation and cognitive performance in CAD patients. Methods: Cognitive performance was measured with a standardized battery of cognitive tests: verbal memory was assessed using the California Verbal Learning Test, 2nd Ed; visuospatial memory using the Brief Visuospatial Memory TestRevised; speed of processing using the Trails Making Test A and the Digit Symbol-Coding subtest of the Weschsler Adult Intelligence Scale; and executive function using the Trails Making Test B and the FAS Verbal Fluency test. Standardized Z-scores of related tests were summed to reflect performance in cognitive domains. Lipid hydroperoxides (LPH), early-stage products of