Browsing by Subject "Developmental Neuroscience"
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Item Activities of Daily Living and Cardiovascular Risk Factors' Impact on Cardiovascular Disease (CVD) and Cognitive Functioning: A Three Stage Longitudinal Model(2005-05-01) Bozo, Ozlem; Guarnaccia, Charles A.; Hall, James; Kelly, KimberlyBozo, Ozlem, Activities of Daily Living and Cardiovascular Risk Factors’ Impact on Cardiovascular Disease (CVD) and Cognitive Functioning: A Three Stage Longitudinal Model. Doctor of Philosophy (Health Psychology), May, 2005, 122 pp., 23 tables, 4 figures, references, 50 titles. The purpose of this study was to examine the longitudinal relationship of daily living (ADL), cardiovascular risk factors, and cardiovascular diseases to predict the future cognitive functioning of older Americans who are between the ages of 51 and 61 at the time of initial assessment. Three waves of the Health and Retirement Study (HRS) database between the years of 1992 and 2002 were examined with path analysis. The longitudinal hypotheses of the study were that (1) ADLs would positively predict future cognitive functioning, (2) ADLs would negatively predict future cardiovascular risk factors, (3) ADLS would negatively predict future cardiovascular diseases, (5) cardiovascular risk factors would negatively predict future cognitive functioning, (6) cardiovascular disease would negatively predict future cognitive functioning, (7) cardiovascular risk factors would mediate the relationship between ADLS and cardiovascular disease, and (8) cardiovascular disease would mediate the relationship between cardiovascular risk factors and cognitive functioning. The results of the analyses indicate that there was no effect of cardiovascular disease on cognitive functioning; however, there were significant effects of cardiovascular risk factors on cognitive functioning that ranged between B=-/021 and B=-/145. Moreover, it was found that cardiovascular risk factors mediate the relationship between ADLs and cognitive functioning, while cardiovascular disease does not. These results suggest that addressing cardiovascular risk factors may be more important than addressing existing cardiovascular disease to protect future cognitive functioning. This shows the importance of primary/secondary prevention versus tertiary interventions.Item Brain Derived Neurotrophic Factor Regulates Müller Cell Survival via MAPK and PI3K Pathways(2003-05-01) Taylor, Sara A.; Agarwal, Neeraj; Wordinger, Robert J.; Pang, Iok-HouTaylor, Sara A., Brain Derived Neurotrophic Factor Regulates Müller Cell Survival via MAPK and PI3K Pathways. Master of Science (Biomedical Sciences), January, 2003, 112 pp., 4 tables, 39 illustrations, bibliography, 68 titles. Purpose: Glutamate has been implicated in many pathologies affecting the Central Nervous System including those in the retina, but the exact nature of the role of glutamate in neuronal degeneration remains unclear. In the retina. Müller cells are resistant to glutamate insults that are normally toxic to other cells of the retina, however the molecular and biochemical mechanisms that control their death or survival are not well understood. We used a series of pharmacological inhibitors and molecular biology agents on cultured Müller cells to dissect two key signaling pathways normally involved in cell survival, the Mitogen Activated Protein Kinase – Extracellularly Regulated Kinase (MAPK(ERK) pathway and the Phosphatidylinositide 3 Kinase (PI3K) pathway. Since preliminary data in our laboratory showed that Müller cells upregulate their secretion of neurotrophins including Brain Derived Growth Factor (BDNF) in response to glutamate treatment, we also examined the effect of BDNF on the activation of these two signaling pathways. Methods: Early passaged Müller cells were treated with various concentrations (5 nM -50 μM) of inhibitions of the MAPK(ERK) pathway (GW5074, U0126, and PD98059) or with various concentrations (1-50 μM) of inhibitors of the PI3K pathway (LY294002 or Akt inhibitor) in the presence and absence of 50 ng/ml of BDNF for 24 hours. These experiments were repeated in Müller cells transfected with either NFκB or Bc12 DNA. Cell cultures were then analyzed for surviving cells with an MTS/PMS assay, a colorametric method for determining the number of viable cells in a proliferation assay. Results: The MAPK (ERK) inhibitors PD98059 and GW5074 both resulted in decrease in Müller cell survival. PD98059 did not decrease Müller cell survival until concentrations were high enough to suppress ERK2 phosphorylation. Müller cells transfected with NFκB or Bc12 DNA were able to resist treatment with concentrations of PD98059 that reduced cell number in untransfected cells. The PI3K inhibitor LY294002 also resulted in significant decreases in Müller cell survival in both untransfected cells and cells transfected with NFκB or Bc12 DNA. Treatment with an inhibitor farther down in the PI3K pathway, Akt inhibitor, did not significantly decrease Müller cell survival. Finally, BDNF was not able to increase cell survival in Müller cells treated with PD98059 or U0126, although it did increase the survival of cells treated wit GW5074. BDNF was also able to reverse the decrease in cell survival caused by LY294002 in both untransfected Müller cells or Müller cells transfected with NFκB or Bc12 DNA. Conclusions: Our data shows that Mitogen Activated Protein Kinase – Extracellularly Regulated Kinase (MAPK(ERK) and Phosphatidylinositide 3 Kinase (PI3K) are both essential for Müller cell survival. There is modulation between the pathways and they may interconnected far upstream at a protein previously associated with only the MAPK(ERK) pathway. These results are consistent with a role for both pathways in Müller cell survival.Item Cellular and Molecular Mechanisms that Distinguish the Effects of Progestorone and Medroxyprogesterone Acetate on Neuroprotection(2006-07-28) Kaur, Paramjit; Goldfarb, Ronald; Singh, Meharvan; Agarwal, NeerajKaur, Paramjit. Cellular and Molecular Mechanisms That Distinguish the Effects of Progesterone and Medroxyprogesterone Acetate on Neuroprotection., Doctor of Philosophy, (Pharmacology and Neuroscience), July, 2006, 203 pp., 5 illustrations, 20 figures and bibliography. Women have a higher prevalence for Alzheimer’s disease (AD) than men, suggesting that the precipitous decline in gonadal hormone levels following the menopause may contribute to the risk of developing AD. However, principal results from the Women’s Health Initiative concluded that women taking conjugated equine estrogens combined with medroxyprogesterone acetate (MPA, tradename: Prempro) incurred more harmful than beneficial outcomes versus the placebo group (Rossouw et al., 2002). This dissertation was aimed at determining if the discrepancy between basic science reports and these clinical studies could have been due to the synthetic progestin, MPA. I hypothesized that P4 and MPA differed in their ability to protect against the excitotoxic/oxidative insult, glutamate. Further, I proposed that this difference in neuroprotective potential would be reflected in the difference in the ability of these hormones to elicit key effectors of two neuroprotection-associated signaling pathways, the ERK/MAPK and P13-Kinase pathways. Finally, studies were initiated to evaluate the potential importance of BDNF (brain-derived neurotrophic factor) in mediating the protective effects of P4. I used organotypic explants of the cerebral cortex, and found that both P4 and MPA elicit the phosphorylation of ERK and Akt, two signaling pathways implicated in neuroprotection, with maximal phosphorylation occurring at a concentration of 100 nM. Interestingly, P4 protected against glutamate- induced toxicity however, while an equimolar concentration of MPA (100nM) did not. Further, P4 resulted in an increase in BDNF, while MPA did not. Our data bring into question the relevance of using MPA as a component of hormone therapies in postmenopausal women, and instead, argue that the relevant progestin for use in treating brain-related disorders is progesterone. Collectively, the data presented here suggest that P4 is protective via multiple, and potentially related mechanism, and importantly, its neurobiology is different from the clinically used progestin, MPA.Item Extracellular PACE4 is increased following transient oxygen glucose deprivation in Optic Nerve Astrocytes(2008-05-01) Fuller, John Anthony; Wordinger, Robert J.; Clark, Abbot F.; Krishnamoorthy, Raghu R.Fuller, John Anthony Extracellular PACE4 is increased following transient oxygen glucose deprivation in Optic Nerve Astrocytes. Doctor of Philosophy (Biomedical Sciences), May, 2008, 140 pp., 2 tables, 25 illustrations, bibliography, 218 titles. Primary Open Angle Glaucoma (POAG) is a family of heterogeneous optic neuropathies characterized by progressive retinal ganglion cell (RGC) death that leads to peripheral vision loss and eventually blindness. Various risk factors are associated with glaucoma, however the molecular mechanisms leading to RGC cell death remain unknown. The optic nerve serves as the conduit for the transmission of retinal ganglion action potentials to the brain. The cells that compromise the optic nerve form a scaffold that forms a physical support for the RGC axons. One cell type found throughout the optic nerve and associated with the RGC axon is the optic nerve astrocyte (ONA). Astrocytes are a predominant cell throughout the CNS and are believed to play crucial roles in metabolic, growth factor, and structural support, and respond to protect neurons during injury. The neuronal-glial interface in the optic nerve is poorly understood and believed to plan an important role in POAG pathophysiology, as unmyelenated RGC axons have direct contact with astrocyte processes. IN this study, the subtilisin-like Proprotein Convertases, (SPC) a family of proteases responsible for cleaving a wide variety of protein substrates, were examined in the retina and optic nerve head. PACE4, an SPC found to be secreted and active in the extracellular matrix was found to be highly expressed in the optic nerve, and colocalized to Mϋller cells in the retina and astrocytes in the optic nerve. Exposure of primary optic nerve astrocytes to oxygen-glucose deprivation (OGD) induces an increase in PACE4 mRNA. Furthermore, protein levels of extracellular, processed PACE4 increase following transient ODG, whereas the pro form of the molecule is degraded, and is believed to be chaperoned by the cleaved cysteine rich domain, a product found at high levels in the optic nerve in situ and the ONA in vitro. Due to the extracellular activity of PACE4, we hypothesized that it may regulate the bioactivity of TGF-β2, a growth factor believed to be involved in glaucoma-associated ONH remodeling by inducing the production of extracellular matrix (ECM). When PACE4 is inhibited via siRNA-mediated knockdown, as well as extracellular inactivation, TGF-β2 levels decrease. In addition, fibronectin, a major component of the ECM, is decreased. Furthermore, there is an increase in latent TGF-β2 secreted from the cell. It is therefore possible that PACE4 plays an active role in extracellular growth factor maturation, and may be a central mediator for growth factor bioactivity in the glaucomatous ONA.Item Identification of Oxidized Proteins in Alzheimer's Disease(2002-08-01) Choi, Joungil; Gracy, Robert R.; Harris, B.; Lacko, Andras G.Joungil Choi, Identification of Oxidized Proteins in Alzheimer’s Disease. Doctor of Philosophy (Molecular Biology and Immunology). August, 2002. Pages-110. Tables 8. Figures 24. Oxidative modification of specific proteins is central to the pathology of Alzheimer’s disease (AD). The purpose of this study was to identify the oxidation-sensitive proteins in neuronal cells, fibroblasts from AD subjects, and in the blood of AD patients. In all cases, age-matched non-Alzheimer’s samples were used as controls. Proteomic methods were used to isolate and characterize the oxidized proteins. These included two-dimensional gel electrophoresis, immunolocalization of oxidized proteins and identification by MALDI-TOF mass spectroscopic methods. It was hypothesized that knowledge of these critical oxidation-sensitive proteins would shed light on the underlying mechanism of the disease. In addition, it was postulated that these proteins might prove to be biomarkers for early detection and monitoring the progress of the disease. The results show that two different oxidative stressors (H2O2 generated enzymatically, or the amyloid beta peptide, AB25-35) induce apoptotic cell death and oxidation of specific proteins (heat shock protein 60 and vimentin) in skin fibroblasts from AD subjects and in neuronal cells. In addition, the results indicate that susceptibility of these two proteins to oxidative stress is increased in fibroblasts from AD patients, compared to non-AD controls. Pretreatment with antioxidants (e.g., vitamin E or flavonoids) protect these proteins from oxidative damage. Both heat shock protein 60 and vimentin, have been suggested to function as antiapoptotic proteins. Thus, their oxidative damage could lead to the apoptotic neuronal cell death in Alzheimer’s disease. In the blood plasma of AD subjects, isoforms of fibrinogen gamma chain and alpha-1 antitrypsin were found to be oxidized. These proteins exhibited to a two- to six-fold greater specific oxidation index in plasma from AD subjects when compared to controls. Both of these proteins have been suggested to be implicated in oxidation-mediated damage of inflammation in the AD brain.Item Lifelong vs. Late Life Tocopherol on Learning and Memory in Mice(2004-05-01) McDonald, Shelley R.; Michael Forster; Glenn DillonMcDonald, Shelley R., Lifelong vs. late life tocopherol on learning and memory in mice. Doctor of Philosophy (Biomedical Sciences), May, 2004, 132 pp., 1 table, 14 figures, bibliography, 122 titles. The purpose of these studies was to determine if vitamin E supplementation, a well-studied antioxidant, could improve the cognitive functions of old mice either by preventing age-dependent impairments or reversing age-related dysfunction. Cellular oxidative stress is believed to be a causal factor in senescence, and the brain appears to be particularly susceptible to oxidative damage because of a relatively high rate of reactive oxygen species generation without commensurate levels of antioxidant defenses. If oxidative stress indeed plays a role in age-related brain dysfunction, then it can be predicted that experimental interventions capable of lowering oxidative stress would either prevent or restore function. This was tested using apolipoprotein E-deficient mice, which have an increased susceptibility to neuronal oxidative damage, maintained on 3 different doses (2 mg/kg, 20 mg/kg, or 200 mg/kg/day) of dl-α-tocopheryl acetate (vitamin E) via supplemented food pellets from 8 weeks of age throughout behavioral testing when 6 or 18 mo of age. A separate experiment used wild type mice 24 months of age to examine whether or not a combination of vitamin E (123 mg/kg/day) with coenzyme Q10 (200 mg/kg/day) which leads to higher tissue levels of vitamin E, could improve brain functions in old mice. Mice were tested on multiple behavioral tasks that required utilization of various components of memory and learning, as well as sensorimotor testing. The highest dose of vitamin E prevented the decline of spatial memory in old apolipoprotein E-deficient mice, but did not prevent age-related impairments in learning and memory for discriminated escape. When old wild type mice were treated with the combined vitamin E and coenzyme W10, the mice learned and remembered to avoid a preemptive shock significantly more than old mice treated with vitamin E or coenzyme Q10 alone. A followup experiment with higher doses of coenzyme Q10 alone (250 or 500 mg/kg/day) resulted in no cognitive improvements. No treatments improved sensorimotor performance.Item Met-Enkephalin-Arg-Phe (MERF) and Metabolism of MERF Across the Canine Heart Vascular Bed(2000-08-01) Pearlman, Eric Brian; Barbara Barron; Patricia A. Gwirtz; Michael L. SmithPearlman, Eric B., Met-Enkephalin-Arg-Phe (MERF) and Metabolism of MERF Across the Canine Heart Vascular Bed. Master of Science (Biomedical Science), August, 2000, 37 pp., 3 tables, 11 figures, references, 20 titles. Methionine enkephalin arginine phenylalanine (MERF) has been shown to be co-stored with catecholamines in vesicles. The catecholamines appear to decrease the degradation rate of 3H-MERF in vitro. The aim of this study is to investigate the spillover and metabolism of MERF across the canine heart vascular bed. I hypothesize that 3H-MERF is either degraded in the plasma or taken up and degraded by the heart. I further hypothesize that the exogenous catecholamine, isoproterenol, inhibits or reduces the rate of MERF degradation. Mongrel dogs were anesthetized and instrumented to record cardiovascular parameters, infuse 3H-MERF, and obtain blood samples across the heart. Blood samples were taken before and after stopping 3H-MERF infusion to evaluate kinetics, show steady state, and test the effect of treatments. Steady state concentration of 3H-MERF was observed after 30 min of infusion. Chromatography separated intact from degraded 3H-MERF. Three experimental groups were used: control, propranolol plus isoproterenol, and propranolol only. Blockade of β-receptors was necessary to prevent changes in coronary blood flow. Propranolol bolus (0.2 mg/kg) was administered IV at 50 min. 3 μg/min isoproterenol or 0.5 ml/min normal saline was infused starting at 70 min until the end of sample collection. The 3H-MERF venous-arterial (V-A) difference prior to treatment was negative, indicating degradation in the plasma or uptake and degradation by the heart. The 75 min V-A difference was used to calculate the effect of the infusions on the degradation or uptake of the 3H-MERF; this value was unchanged by any treatment. Spillover of 3H-MERF was significantly lower in the propranolol + isoproterenol dogs (p [less than] 0.05) compared to propranolol only treatment at 75 min. Heart rate was significantly lower for the propranolol only group compared to control. Blood pressure and change in coronary flow were unchanged. In conclusion, isoproterenol does not affect the metabolism of 3H-MERF across the canine heart vascular bed. Propranolol, however, does increase the intact 3H-MERF in the plasma, but additional β adrenergic blockade agents need to be investigated to determine the mechanism by which this takes place.Item The Effect of Late-Life Antioxidant Supplementaion on Brain Function(2007-10-01) Shetty, Ritu A.; Forster, Michael J.; Sumien, Nathalie; Singh, MeharvanShetty, Ritu A., The effect of late-life antioxidant supplementation on brain function. Doctor of Philolosophy (Biomedical Sciences), October, 2007, 229 pp., 5 tables, 18 figures, bibliography, 284 titles. Purpose: Aging is associated with mild to moderate loss in brain function over time. These functional losses are thought to involve reversible changes disrupting important cellular signaling processes. One of the theories that proposes to explain the reversible losses of function is the ‘oxidative stress’ hypothesis of aging. According to the oxidative stress hypothesis, there is an inherent cellular imbalance between production of oxidants and antioxidative defenses that increases with age and that leads to an increase in oxidative damage to macromolecules that are involved in crucial cell functions. Previous studies have established a link between these cellular changes associated with aging and the impairments in cognitive and psychomotor function. Further it has also been suggested that dietary interventions can modulate the level of oxidative stress, reducing oxidative damage and perhaps even ameliorate age-related dysfunction. Most interventions have been implemented relatively early in life and maintained until old age. However, the current studies were based on the rationale that interventions initiated in late-life could potentially lower oxidative damage and thereby alter cellular components responsible for functional impairments. Methods: In study I, separate groups of young (4 months) and old mice male C57BL/6 (18 months) were fed a control diet or a diet supplemented with low (105 mg/kg/day) or high (368 mg/kg/day) concentrations of CoQ10 for a period of 15 weeks. After 6 weeks on the diets, the mice were subjected to a battery of age-sensitive behavioral tests. In study II, separate groups of male C57BL/6 young mice aged 3-4 months and old mice 17-18 months (total of n=124) were fed ad libitum either a control diet (cyclodextrin in base diet), or the same diet supplemented with D- α-tocopheryl acetate (Toc) (200 mg/kg body wt/day), or with CoQ10 (148 mg/kg body wt/day) or a diet containing a combination of CoQ and Toc (200 mg/kg body wt/day + 148 mg/kg body wt/day) for a period of 13-14 weeks. In both studies mice were subjected to a battery of behavioral tests that required utilization of various component of memory and learning and sensorimotor reflexes. Results: In study I, low CoQ10 failed to improve cognitive and psychomotor function in old mice. However, the high CoQ10 marginally helped the old mice to navigate in the swim maze task with greater efficiency than control mice but did not affect their performance in probe trials. Conversely, the high CoQ10 diet selectively impaired the spatial performance in young mice in probe trials. The results from study I indicated that intake of CoQ10 initiated in late-life had minimal beneficial effects on behavior function. In study II, an age-associated decline of behavioral functioning was observed; however CoQ10 treatment failed to improve the performance of mice in any of the age-sensitive tests. Moreover, young mice supplemented with a high CoQ diet performed poorly in the probe trial in a swim maze task, suggesting a possible deleterious effect. The results from study II indicated that there was a significant improvement in performance of old mice in the coordinated running and the learning ability in discriminated avoidance task when supplemented with Toc or with a combination of CoQ10 and Toc. Conclusions: In conclusion, these studies suggest that benefits of single antioxidant supplementation when initiated late in life are limited; however dietary supplementation with a combination of antioxidants has a greater impact in reversing age-related decline in behavioral function.Item The Effects of Short-Term Intermittent Hypoxic Apneas on Sympathetic Nerve Activity and the Chemoreflex Control of Sympathetic Nerve Activity in Humans(2004-05-01) Cutler, Michael J.; Smith, Michael L.; Raven, Peter B.; Downey, H. FredCutler, Michael J., The Effects of Short-Term Intermittent Hypoxic Apneas on Sympathetic Nerve Activity and the Chemorelex Control of Sympathetic Nerve Activity in Humans. Doctor of Philosophy (Integrative Physiology), May 2004. Obstructive sleep apnea is associated with sustained elevation of muscle sympathetic nerve activity (MSNA) and altered chemoreflex control of MSNA both of which likely play an important role in the development of hypertension in these patients. Hypoxia is postulated to be primary stimulus for elevated daytime MSNA and altered chemoreflex control of MSNA both of which likely play an important role in the development of hypertension in these patients. Hypoxia is postulated to be the primary stimulus for elevated daytime MSNA and altered chemoreflex control of MSNA in OSA patients. Recently, short-term exposure to hypoxia was shown to produce sustained elevation of MSNA. Therefore, we studied the effects of 20 min of intermittent voluntary hypoxic apneas (to mimic OSA) on MSNA and the chemoreflex control of MSNA during 180 min post exposure. Also, we compared MSNA and chemoreflex control of MSNA for 180 min following either 20 min of intermittent voluntary hypoxic apneas, hypercapnic hypoxia, or isocapnic hypoxia. Consistent with our hypotheses, both total MSNA and MSNA burst frequency were elevated following 20 min of intermittent hypoxic apnea compared to baseline (p [less than] 0.05). Both total MSNA and MSNA burst frequency remained elevated throughout the 180 min recovery period and were statistically different from time control subjects throughout this period (p [less than] 0.05). Additionally, a significant main effect for chemoreflex control of SNA was observed following 20 min of intermittent hypoxic apneas (p [less than] 0.001). Specifically, the MSNA response to a single hypoxic apnea was attenuated 1 min post exposure compared to baseline (p [less than] 0.001), became augmented within 30 min of recovery, and remained augmented through 165 min of recovery (p [less than] 0.05). Finally, comparison of treatment groups (hypoxic apnea, hypercapnic hypoxia, and isocapnic hypoxia) revealed no differences in resting MSNA (p=0.50) and the chemoreflex control of MSNA (p=0.69) during recovery. Therefore, these data support the hypothesis that short-term exposure to intermittent hypoxic apneas resulted in sustained elevation of MSNA and altered chemoreflex control of MSNA. Furthermore, these responses appear to be mediated by hypoxia.Item The Role of Advanced Glycation End Products in Brain Aging(2007-10-01) Thangthaeng, Nopporn; Michael J. Forster; Tina MachuThangthaeng, Nopporn, The Role of Advanced Glycation End Products in Brain Aging. Doctor of Philosophy (Biomedical Sciences), October, 2007, 178 pp., 9 tables, 6 figures, bibliography, 213 titles. Glycoxidation is a process of post-translational modification of proteins, involving both glycation and oxidation that ultimately generated advanced glycation end products (AGEs). Glycoxidation, which pay promote oxidative stress and disrupt protein structure and function, is hypothesized to be responsible for pathological conditions related to aging, diabetes, neurodegenerative diseases, and degenerative ophthalmic diseases. Previous studies have demonstrated that AGEs accumulate in the brains of aged animals and humans, yet few studies have directly addressed the possibility that AGEs are a cause of age-related brain dysfunction. Therefore, the overall purpose of the present studies was to examine the role AGEs in normal brain again and the associated decline in cognitive and psychomotor function. In order to achieve the goals, two different approaches were taken. The first approach involved (i) determining whether or not AGEs accumulated in different regions of the brain as a function of age and (ii) determining whether these changes were correlated with individual differences in the ability of old mice to perform in tests of cognitive and psychomotor function. Age-associated accumulation of CML, a predominant form of AGEs in vivo, and expression of receptor for AGEs (RAGE) protein, inferred from densitometry quantification of immunoblots in different regions of the brain, were assessed by comparing groups of 8-or 25-month old mice. The 25-month-old mice were administered a series of behavioral tests to assess cognitive and psychomotor function prior to assessment of glycation status. In the second approach, groups of mature (6 mos) and older mice (18 mos) were fed with a control diet or a diet enriched with galactose (49% of caloric content), an intervention that was expected to promote formation of AGEs. The mice were subsequently tested for impairment of their cognitive and psychomotor functions after 8 weeks on the assigned diet. Upon completion of the behavioral tests (after 14 weeks on diet), amounts of CML and RAGE protein were assessed through densitometric analyses of the immunoblots. The main findings from the first approach were that (i) there was a robust increase in CML content and expression of RAGE protein in the aged mouse brain that occurred in a region-specific manner; (ii) the relative amounts of CML and RAGE were not closely associated with the degree of age-related impairment of mice tested for brain function. The main findings from the second approach were that high dietary galactose: (i) failed to induce aged-like behavioral impairments in young/mature mice; (ii) exacerbated age-related impairment of some psychomotor functions and (iii) had no significant effects on glycation status or oxidative damage. Comparison of the experimental outcomes from the first and second approaches was complicated by a difference in the fat content of the diets fed to the mice in the two studies, which had an apparent effect on the amounts of AGEs and protein oxidation present in young mice. However, considering the results of the two studies independently warrants the following conclusions: (i) Amounts of AGEs do not predict individualized brain aging as assessed by neurobehavioral impairment and may instead by largely reflective of chronological age. (ii) Diets enriched with galactose may produce deleterious effects in older mice that do not involve a change in oxidative damage or glycation status. Overall, these studies provide little support for a specific role of glycoxidation in normal brain aging. It is impossible that the extent of accrual of AGEs in the normally aging brain is insufficient to affect cellular function, whereas larger accumulations of AGEs may be associated with various pathological conditions discussed in the literature.