Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of human senile dementia. Alzheimer’s represents a significant public health concern, having widespread social and economic implications. Consequently, protocols for early detection and therapeutic intervention (both behavioral and pharmacologic) constitute important targets for medical investigation. Furthermore, contemporary research depends upon comprehensive neurobehavioral assessment and advanced statistical and computational analytic methodologies for characterizing AD-associated sensorimotor and cognitive impairment, as well as evaluating therapeutic efficacy. This dissertation introduces data mining-based techniques (decision trees, neural networks, support vector machines) for behavioral analysis in both nontransgenic and Alzheimer’s transgenic mice, to evaluate the cognitive benefits of long-term caffeine treatment. Both treatment and transgenic effects are identified through advanced statistical (discriminant analysis) and data mining approaches. In addition, a novel mouse-based cognitive assessment paradigm, adapted from a human interference learning AD-diagnostic protocol, is implemented to evaluate both genetic (GRK5) and therapeutic (GM-CSF) effects in mice, against an Alzheimer’s transgenic background. Data mining techniques are shown to be comparable to con ventional statistical analyses, often providing complementary diagnostic information. Indeed, comparisons between data mining-based and multivariate statistical analyses, with respect to groupwise discriminability, support the use of both methodologies in neurobehavioral research. Future work involving both data mining-based and multivariate statistical analyses of cognitive-behavioral data is discussed, emphasizing the need for longitudinal studies, repeated-measure designs, and spatiotemporal modeling for evaluating the time-course of both human AD and AD-like pathology in transgenic mouse models.

Deteriorations in cognitive functioning and sleep are the inevitable parts of the ageing process, and they are two very common complaints among the elderly population. Given their high relevance and great impact on daily functioning, many studies have attempted to address the associations of sleep problems and cognitive functioning with ageing, yet the direction of associations remained unclear. Several recent studies suggested that caffeine, a common psychostimulant present in coffee and tea, might have a beneficial effect on agerelated decline in cognitive functioning. Nonetheless, the dose-dependent effect of caffeine intake on specific domains of cognitive functioning, and the potential cost of compromised nocturnal sleep at high dose of caffeine remained to be investigated. In view of the lack of study on identifying the correlation and interaction between sleep, cognitive functioning, caffeine consumption habit, and age, this thesis reported two studies that clarified these relationships in the elderly population. Furthermore, the studies explored the possibility to utilize sleep and caffeine as a regimen to improve daytime cognitive functioning in the older population. Study 1 was a retrospective study that aimed to examine the relationship between sleep, habitual caffeine consumption, cognitive functioning, and mood in the two different age groups, the young adult and the elderly. Eighty-nine healthy elderly and forty-three healthy young adults participated in this study and completed a battery of neuropsychological assessment and a set of questionnaires. Findings revealed changes in multiple domains of sleep and cognitive functioning upon ageing. The age-related differences in sleep and cognitive functioning were correlated. Moreover, result suggested that regular caffeine consumption has a dose-dependent beneficial effect on cognitive functioning, but the effect was only observed in female. Study 2 was built on the relationship between sleep, cognitive functioning, and caffeine as found in Study 1. It aimed to investigate the effect of caffeine and daytime nap on the cognitive functioning in the healthy elderly adopting a repeated measure, double-blind, placebo-controlled design. Twenty-four healthy elderly were recruited for this study, and each of them were required to attend four experimental sessions with a one-week intersession interval. In each session, participants were required to take a rest or take a nap with or without a certain dosage of caffeine in the afternoon. Comparisons on their cognitive performance before and after the rest/ nap revealed an effect of nap and caffeine on improving subjective feeling of sleepiness and fatigue. Behavioural measurements revealed no effect on daytime nap on cognitive functioning, yet specific sleep stage and certain sleep oscillations were associated with post-nap changes in cognitive functioning. In summary, the present studies demonstrated the associations of sleep and caffeine consumption with cognitive functioning in the elderly. Habitual caffeine consumption was associated with a female-specific beneficial effect on cognitive functioning. Furthermore, daytime nap combined with the use of acute dose of caffeine might not enhance cognitive functioning, but could improve mood and well-being in the elderly. Findings from present studies suggested that further research could explore ways to maximise the benefit of napping in the elderly. / published_or_final_version / Psychology / Doctoral / Doctor of Philosophy

The influence of vitamin C on the pharmacokinetics of caffeine was investigated in ten elderly males, age 66 to 86 years. Caffeine (4 mg kg⁻¹) was administered intravenously on three different occasions over a seven-week period: before vitamin C restriction, after approximately four weeks of vitamin C restriction (15 mg dietary intake per day), and after two weeks of vitamin C supplementation (500 mg orally, twice daily). Blood and urine samples were collected over a 48-hour period following each caffeine administration. The plasma half-life (t₁/₂), rate constant of elimination (K), apparent volume of distribution (V), total body clearance (TBC), renal clearance (RC), and metabolic clearance (MC) of caffeine were determined. Simultaneous plasma (PVC), whole blood (WBVC), and leukocyte (WBCVC) vitamin C concentrations were obtained. All of the mean vitamin C values determined at the first kinetic trial (KT-1) were within the normal ranges for the respective biologic fluid or tissue. All of the mean vitamin C values changed significantly during the study; decreasing to below the normal ranges by the second kinetic trial (KT-2) following dietary vitamin C restriction, and increasing to the normal ranges by the third kinetic trial (KT-3) following vitamin C supplementation. All of the decreases and increases in the individual and average vitamin C concentrations paralleled the observed decreases and increases in the daily vitamin C intake. None of the caffeine pharmacokinetic parameters evaluated changed significantly during the study. The mean rate constant of elimination was approximately 0.15 hr⁻¹, the average plasma half-life was approximately 4.5 hours, and the mean apparent volume of distribution was approximately 500 ml kg⁻¹ for all three kinetic trials. The average total body, renal, and metabolic clearances were approximately 76.9, 1.3, and 76.0 (ml hr⁻¹)kg⁻¹, respectively, for all three kinetic trials. With the exception of V and TBC, the various pharmacokinetic characteristics investigated were in general agreement with data reported for younger subjects. The average apparent volume of distribution determined at any of the kinetic trials was about 16% lower than the value reported for young, healthy subjects. Similarly, the mean total body clearance observed was about 21% lower than that observed in young, healthy subjects. Since the average elimination rate constant observed in these elderly subjects is similar to the values observed in younger subjects and since TBC is equal to the product of V times K, the reduced TBC observed in this study appears to be due to the reduction in V, rather than to a decrease in the intrinsic metabolic capacity of the liver with aging. No relationship between vitamin C intake and/or body levels and the pharmacokinetics of caffeine was observed. These results indicate that the elimination of caffeine in the elderly is not affected significantly by the concentrations of vitamin C achieved during the study.

Caffeine, a mild central nervous system stimulant, is a natural component of common hot and cold beverages like coffee, tea, sodas and cocoa. Animal studies have demonstrated caffeine’s teratogenic effects when administered at high concentrations; however, epidemiologic studies have yielded inconsistent results in humans. Because caffeine containing beverages are commonly consumed by pregnant women, we examined the prevalence of use and explored possible associations of maternal caffeine consumption with cardiovascular malformations in 3,274 cases matched with 3,519 controls enrolled in the 1981-89 “Baltimore-Washington Infant Study,” a population-based case-control investigation. We explored several key aspects of the quality of and distribution of measurements of caffeine consumption among mothers in the study population. We concluded with recommendations for refining data collection to reduce potential bias associated with assessing both caffeine content and changes in caffeine consumption during pregnancy in order to inform future research studies and birth defects/adverse birth outcomes surveillance programs.

No description available.

While considerable information exists regarding the independent effects of caffeine and psychological stress on cardiovascular activity, there is relatively little information on their combined effects. Since caffeine may enhance cardiovascular responsivity to psychological stress, research on hemodynamic responses to caffeine-stress combinations may help elucidate mechanisms of hypertension development. In a series of studies, regular consumers of caffeine were exposed to laboratory and naturalistic stressors with and without prior caffeine intake. Among the findings were (1) caffeine and stress produced additive increases in blood pressure, (2) caffeine appears to potentiate beta-adrenergic responsivity to active coping, but not passive coping, stressors, (3) caffeine enhanced emotional responses to stress, and (4) cardiovascular responses to caffeine and stress in a naturalistic setting were similar to those observed in the laboratory. These results indicate that caffeine may enhance cardiovascular and psychological responses to stress, and that these responses may contribute to risk for essential hypertension.

Caffeine, one of the most commonly consumed substances worldwide, acts as a biogenic stressor and elicits both cardiovascular and endocrine stress responses. The most commonly described endocrine stress response is the hypothalamic-pituitary-adrenal (HPA) axis, whose final product is cortisol. Cortisol is well described as an indicator of stress levels, and it may be elevated chronically in persistently stressful situations. Its subsequent effects include blood pressure elevation, which is an indicator of cardiovascular stress reactivity. Research shows that cardiovascular and endocrine stress responses attenuate—albeit incompletely—with habitual caffeine consumption. However, when caffeine consumption and situational stressors are combined, stress reactivity is potentiated, raising concerns about long-term effects in populations who are regularly exposed to both. Numerous sex-related factors complicate this area of research in female cohorts. Endocrine considerations, especially relating to fluctuating estradiol levels, are well known to affect both caffeine metabolism and stress reactivity. Prior studies, ranging from biochemical to epidemiological levels, have identified variability in caffeine metabolism and stress reactivity attributable to menstrual cycle phase and recent pregnancy. Cardiovascular stress reactivity patterns differ, furthermore, between males and females, a reality that translates to differences in cardiovascular disease risk and forms a critical area of future research with broad public health implications. Based on extensive review of caffeine metabolism and stress reactivity literature, focusing on studies relevant to young females with varying habitual levels of caffeine consumption, I designed a study proposal to further characterize these physiological stress responses within this demographic. The core goal of the proposed study is to assess changes in plasma free cortisol concentration and blood pressure following an acute dose of caffeine (200 mg) at peak (40 min) and elimination half-life (160 min) caffeine plasma concentration time points. Average daily caffeine consumption (low, medium, or high) and menstrual cycle phase were included as additional parameters of interest in order to further characterize interactions within the selected demographic.

The intent of this thesis was to study the effects of caffeine ingestion on substrate utilization and muscle metabolism during exercise, as reflected by endurance time to exhaustion. For this purpose, seven trained cyclists performed work bouts at 80% of maximal oxygen consumption to exhaustion after ingestion of caffeine (CAF trial) end under control (CON trial) conditions.Although the work time to exhaustion was not significantly different between the CAF trial, 91.8 (S.E. ± 7.7) min and the CON trial, 85.2 (S.E. ± 10.5) min, five of he subjected did show an average 18% increase in performance following ingestion of 330 mg caffeine. Since there was no elevation of FFA prior to exercise, it was expected that no muscle glycogen sparing would occur during the first 30', 41.7 (S.E. ± 6.1) mM/kg in the CAF trial and 42.1 (S .E. + 6.6) mM/kg in the CON trial. Serum glycerol concentration was significantly (P< .05) during the CAF trial at 10' and 30'. R values were significantly lower during the CAF trial, .87 (S.E. ± .01) than the CON trial, .91 (S.E. ± .01) at exhaustion. Significantly lower (p<.05) perceived exertion ratings were also observed during the CAF trial. These data suggest a positive effect on endurance exercise performance following caffeine ingestion.

The purpose of the present study was to elucidate if caffeine ingestion reduced perception of effort at submaximal intensities during a maximal exercise test. A secondary purpose of this study was to examine the role of a single nucleotide polymorphism (SNP) at intron 1 of cytochrome P-450 gene in modulating caffeine’s influence on ratings of perceived exertion (RPE) at the same submaximal exercise intensities. Twelve healthy men (age: 24±1 yr., BMI: 23.9±1.2 kg.m2) volunteered to participate in the present study. Subjects consumed 6 mg.kg-1 of USP grade caffeine in 200ml of non-caloric, coloured and flavoured water, or a placebo-matched drink in a single-blind, randomised and crossover style design. Subjects remained seated for 1 hour after consuming the assigned drink, and subsequently completed an incremental maximal exercise test on a bicycle ergometer, which started at 0 Watts for 1 minute and increased by 25 Watts per minute until volitional exhaustion. RPE was reported every third minute during the test. DNA was obtained from whole blood samples and genotypes were determined using previously described methods. Similar to previous studies looking at this SNP, subjects were categorised into groups of AA homozygotes and C allele carriers for statistical analyses between genotypes. Two-way repeated measures ANOVA’s were performed (Treatment × Genotype) for RPE responses at submaximal workloads up to 300 Watts. Significant results were followed up using the bonferroni post-hoc method. There were no significant differences between individuals homozygous for the A variant and C allele carriers for age, height, weight, body mass index (BMI), and VO2max. A significant Time × Treatment interaction was observed (F=5.804, p<0.05) for the rate of increase in RPE between trials. A significant Treatment × Genotype interaction was also found (F=5.714, p<0.05), by which C allele carriers exhibited greater reductions in RPE during the caffeine trial compared to AA homozygotes. The findings of the present study indicate that perception of effort is reduced in individuals who metabolise caffeine at a slower rate (i.e. in C allele carriers). It is postulated that AA homozygotes do not experience reductions in RPE due to a greater cardiovascular workload and enhanced CNS excitability following caffeine ingestion / School of Physical Education, Sport, and Exercise Science

The study was designed to determine what type of potentiation,.if any, occurred between caffeine and acetazolamide. Caffeine (75 mg/kg) and/or acetazolamide (200, 1000, or 1500 mg/kg) were administered to pregnant C57BL/6J dams on day 9 of gestation. Fetuses were removed on the eighteenth day of gestation via cesarean section and examined for gross morphological malformations using a Bausch & Lomb SKV1070P dissecting microscope. Treatment with HD-ACZM and HD+CAFF resulted in a reduction of fetal weight. Maternal exposure to MD-ACZM and HD-ACZM caused a statistically significant (P < .001) and dose-dependent increase in the percent of C57BL/6J fetuses with ectrodactyly along with increased severity of the defects displayed (relative to controls). An increase in the number of ectrodactylous fetuses and the severity of defects was also observed in all groups administered caffeine and acetazolamide, reaching statistical significance in the MD+CAFF and HD+CAFF groups (P < .001). Because potentiation of the teratogenic effects of acetazolamide was exhibited only in the MD+CAFF vs. MD-ACZM groups, the type of potentiation occurring between caffeine and acetazolamide can not be determined. / Department of Physiology and Health Science