Teodoro Bottiglieri Ph.D.

Spratlen, M. J., M. Grau-Perez, J. G. Umans, J. Yracheta, L. G. Best, K. Francesconi, W. Goessler, T. Bottiglieri, M. V. Gamble, S. A. Cole, J. Zhao and A. Navas-Acien (2019). “Targeted metabolomics to understand the association between arsenic metabolism and diabetes-related outcomes: Preliminary evidence from the Strong Heart Family Study.” Environ Res 168: 146-157.

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BACKGROUND: Inorganic arsenic exposure is ubiquitous and both exposure and inter-individual differences in its metabolism have been associated with cardiometabolic risk. A more efficient arsenic metabolism profile (lower MMA%, higher DMA%) has been associated with reduced risk for arsenic-related health outcomes. This profile, however, has also been associated with increased risk for diabetes-related outcomes. OBJECTIVES: The mechanism behind these conflicting associations is unclear; we hypothesized the one-carbon metabolism (OCM) pathway may play a role. METHODS: We evaluated the influence of OCM on the relationship between arsenic metabolism and diabetes-related outcomes (HOMA2-IR, waist circumference, fasting plasma glucose) using metabolomic data from an OCM-specific and P180 metabolite panel measured in plasma, arsenic metabolism measured in urine, and HOMA2-IR and FPG measured in fasting plasma. Samples were drawn from baseline visits (2001-2003) in 59 participants from the Strong Heart Family Study, a family-based cohort study of American Indians aged >/=14 years from Arizona, Oklahoma, and North/South Dakota. RESULTS: In unadjusted analyses, a 5% increase in DMA% was associated with higher HOMA2-IR (geometric mean ratio (GMR)= 1.13 (95% CI: 1.03, 1.25)) and waist circumference (mean difference=3.66 (0.95, 6.38). MMA% was significantly associated with lower HOMA2-IR and waist circumference. After adjustment for OCM-related metabolites (SAM, SAH, cysteine, glutamate, lysophosphatidylcholine 18.2, and three phosphatidlycholines), associations were attenuated and no longer significant. CONCLUSIONS: These preliminary results indicate that the association of lower MMA% and higher DMA% with diabetes-related outcomes may be influenced by OCM status, either through confounding, reverse causality, or mediation.

Ross, R. D., R. C. Shah, S. Leurgans, T. Bottiglieri, R. S. Wilson and D. R. Sumner (2018). “Circulating Dkk1 and TRAIL Are Associated With Cognitive Decline in Community-Dwelling, Older Adults With Cognitive Concerns.” J Gerontol A Biol Sci Med Sci 73(12): 1688-1694.

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Background: Osteoporosis and Alzheimer’s disease are common diseases of aging that would seem to be unrelated, but may be linked through the influence of bone-derived signals on brain function. The aim of the current study is to investigate the relationship between circulating levels of bone-related biomarkers and cognition. Methods: The population included 103 community-dwelling older individuals with memory concerns but without cognitive impairment. A global cognition summary measure was collected at baseline and 6, 12, and 18 months post-enrollment by converting raw scores from 19 cognitive function tests to z-scores and averaging. Baseline plasma concentrations of bone-related biomarkers, including undercarboxylated, carboxylated, and total osteocalcin, parathyroid hormone, C-terminal telopeptide of collagen 1 (CTX-1), procollagen type 1 amino-terminal propeptide, osteoprotegrin, osteopontin, Dickkopf WNT signaling pathway inhibitor 1 (Dkk1), sclerostin, and amyloid beta peptides (Abeta40 and Abeta42), were measured. Results: Using sex, age, and education-adjusted mixed-effects models, we found that baseline levels of TNF-related apoptosis-inducing ligand (TRAIL; p < .001), Dkk1 (p = .014), and CTX-1 (p = .046) were related to the annual rate of change of global cognition over the 18 month follow-up. In cognitive domain-specific analysis, baseline TRAIL was found to be positively related to the annual rate of change in episodic (p < .001) and working memory (p = .016), and baseline Dkk1 was positively related to semantic memory (p = .027) and negatively related to working memory (p = .016). Conclusions: These results further confirm the link between bone and brain health and suggest that circulating levels of bone-related biomarkers may have diagnostic potential to predict worsening cognition.

Arora, K., J. M. Sequeira, J. M. Alarcon, B. Wasek, E. Arning, T. Bottiglieri and E. V. Quadros (2018). “Neuropathology of vitamin B12 deficiency in the Cd320(-/-) mouse.” FASEB J Oct 10: [Epub ahead of print].

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In humans, vitamin B12 deficiency causes peripheral and CNS manifestations. Loss of myelin in the peripheral nerves and the spinal cord (SC) contributes to peripheral neuropathy and motor deficits. The metabolic basis for the demyelination and brain disorder is unknown. The transcobalamin receptor-knockout mouse ( Cd320(-/-)) develops cobalamin (Cbl) deficiency in the nervous system, with mild anemia. A decreased S-adenosylmethionine: S-adenosylhomocysteine ratio and increased methionine were seen in the brain with no significant changes in neurotransmitter metabolites. The structural pathology in the SC presented as loss of myelin in the axonal tracts with inflammation. The sciatic nerve (SN) showed increased nonuniform, internodal segments suggesting demyelination, and remyelination in progress. Consistent with these changes, the Cd320(-/-) mouse showed an increased latency to thermal nociception. Further, lower amplitude of compound action potential in the SN suggested that the functional capacity of the heavily myelinated axons were preferentially compromised, leading to loss of peripheral sensation. Although the metabolic basis for the demyelination and the structural and functional alterations of the nervous system in Cbl deficiency remain unresolved, the Cd320(-/-) mouse provides a unique model to investigate the pathologic consequences of vitamin B12 deficiency. -Arora, K., Sequeira, J. M., Alarcon, J. M., Wasek, B., Arning, E., Bottiglieri, T., Quadros, E. V. Neuropathology of vitamin B12 deficiency in the Cd320(-/-) mouse.

Wasek, B., E. Arning and T. Bottiglieri (2018). “The use of microwave irradiation for quantitative analysis of neurotransmitters in the mouse brain.” J Neurosci Methods 307: 188-193.

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BACKGROUND: Assessing neurotransmitter metabolism in the brain is essential in studying the effects of drugs, dietary modification and characterizing transgenic mouse models of human neurodegenerative diseases. Regional brain concentrations of parent neurotransmitters and related metabolites are informative and provide a snap shot of the steady-state levels. The choice in method of sacrificing mice may differ from one laboratory to another, and the technique in removal of brain may have limitations depending on speed in which tissue can be dissected and frozen to prevent post-mortem changes. NEW METHODS: In order to better assess neurotransmitter metabolism in an effective and standardized manner we evaluated microwave irradiation as a method of sacrificing mice. Mice were sacrificed by CO2 asphyxiation followed by cervical dislocation or microwave irradiation at 4 Kw for 1.1s. Brain tissue was harvested into five regions and stored at -80 degrees C until analysis by either LC-MS/MS for acetylcholine, choline and GABA, or HPLC-EC for dopamine, serotonin and norepinephrine and related metabolites. RESULTS: The results of our study showed considerable differences in the levels of neurotransmitters between the two methods of sacrifice. Overall, the concentrations of neurotransmitters were higher in mice sacrificed by microwave irradiation, except for GABA, which was lower. COMPARISON WITH EXISTING METHOD(S): Previous microwave irradiation studies employed presently outdated equipment and neurotransmitter analysis methods, and were not as comprehensive. CONCLUSIONS: The combination of microwave irradiation with LC-MS/MS and HPLC-EC detection allows accurate and sensitive measurement of several neurotransmitter systems in discrete mouse brain regions.

Wasek, B., E. Arning and T. Bottiglieri (2018). “The use of microwave irradiation for quantitative analysis of neurotransmitters in the mouse brain.” J Neurosci Methods. May 23. [Epub ahead of print].

Full text of this article.

BACKGROUND: Assessing neurotransmitter metabolism in the brain is essential in studying the effects of drugs, dietary modification and characterizing transgenic mouse models of human neurodegenerative diseases. Regional brain concentrations of parent neurotransmitters and related metabolites are informative and provide a snap shot of the steady-state levels. The choice in method of sacrificing mice may differ from one laboratory to another, and the technique in removal of brain may have limitations depending on speed in which tissue can be dissected and frozen to prevent post-mortem changes. NEW METHODS: In order to better assess neurotransmitter metabolism in an effective and standardized manner we evaluated microwave irradiation as a method of sacrificing mice. Mice were sacrificed by CO2 asphyxiation followed by cervical dislocation or microwave irradiation at 4 Kw for 1.1s. Brain tissue was harvested into five regions and stored at -80 degrees C until analysis by either LC-MS/MS for acetylcholine, choline and GABA, or HPLC-EC for dopamine, serotonin and norepinephrine and related metabolites. RESULTS: The results of our study showed considerable differences in the levels of neurotransmitters between the two methods of sacrifice. Overall, the concentrations of neurotransmitters were higher in mice sacrificed by microwave irradiation, except for GABA, which was lower. COMPARISON WITH EXISTING METHOD(S): Previous microwave irradiation studies employed presently outdated equipment and neurotransmitter analysis methods, and were not as comprehensive. CONCLUSIONS: The combination of microwave irradiation with LC-MS/MS and HPLC-EC detection allows accurate and sensitive measurement of several neurotransmitter systems in discrete mouse brain regions.