<p>Excess sodium (Na) intake is directly related to hypertension and an increased risk of developing many chronic diseases, but there is currently no method to directly quantify Na retained in the body. Because of this, the locations of Na storage and its exchange mechanisms are not well known. This information is critical for understanding the impact of increased Na intake in modern diets. In order to non-invasively quantify Na in bone and soft tissue, a compact deuterium-deuterium (DD) neutron generator-based <i>in vivo</i> neutron activation analysis (IVNAA) system was developed. MCNP was used to design a custom irradiation assembly to maximize Na activation in hand bone while minimizing dose. In order to test the system, live pigs were used. Two 100% efficient high purity germanium (HPGe) detectors collected Na-24 counts over 24 hours post irradiation. From the pig studies, a two-compartment model of exchange was developed to quantify Na in bone and in soft tissue. The right legs of four live pigs, two on a low Na diet and two on a high Na diet, both for 14 days, were irradiated inside the customized irradiation cave for 10 minutes (45 mSv dose to the leg) and then measured with the HPGe detectors. The spectra were analyzed to obtain the net Na counts at different time points. Analysis shows exponential decrease of Na in the leg during the first one hour of measurement, while the change was minimal at the second hour, and the counts were stabilized at the second and third 2 hour measurements, taken 7 and 21 hours post irradiation. Bone Na and soft tissue Na concentrations were calculated using calibration lines created with bone and soft tissue equivalent Na phantoms as well as the parameters obtained from the two-compartment model. The results show that the difference in bone and soft tissue Na between the pigs on high vs low Na diets was significant. With these results, we conclude that DD neutron generator-based IVNAA can be used to accurately quantify Na in bone and soft tissue <i>in vivo </i>and the system is a potential valuable tool for nutrition studies.</p>

<p>Aluminum (Al) is the third most abundant metal on the earth’s surface. An association of Al with Alzheimer’s disease has been suggested, but, given limited human evidence, is controversial. It is possible that exploration of long-term, or cumulative, exposure to Al will help clarify this debate. Therefore, our study hypothesis was that occupational exposure to Al, particularly long-term exposure, is associated with adverse cognitive and olfactory outcomes. </p><p>Biomarkers are important tools in epidemiologic research; however, the reliability and quality of various biomarkers may vary. Therefore, in Chapter 2, we reviewed current evidence on Al biomarkers with the goal to synthesize current understanding regarding their utility for use in research. Our review evaluated 78 papers which discussed various biomarkers of Al exposure. Limited evidence is currently available for Al in nails, hair, breastmilk, saliva and semen. Although they have more daily variation than other biomarkers, blood Al concentrations may differentiate between exposed and non-exposed groups. Unlike blood Al, Al concentrations in both urine and bone are not subject to daily fluctuations. Bone Al appears able to quantify long term Al exposure. Therefore, the use of <i>in vivo</i>neutron activation analysis (IVNAA), a novel bone biomarker, can potentially represent cumulative Al exposure. </p><p>In Chapter 3, we evaluated the hypothesis that the correlation between bone and CEI measurements will be higher than the correlation between bone with fingernail. A cross-sectional cohort of 61 ferroalloy and manufacturing factory workers from Zunyi, China were used in this secondary analysis. Correlations of bone Al with other Al measures (fingernail and cumulative exposure index (CEI)) were assessed for 43 of the factory workers who had bone Al samples. Fingernail samples were analyzed using inductively coupled plasma mass spectrometry. Bone measurements were taken with a compact IVNAA developed by our research team. CEI was calculated as CEI_i=, where C_iis estimated Al exposure based on job title (low/medium/high) and Y_iis the years employed. The CEI was calculated for the prior 5, 10, 15, 20 years and lifetime work history. Median Al values were: 34.4 mg/g (IQR=46) fingernail; 15 mg/g (IQR=28) bone; and 26 (IQR=21) total CEI. Adjusting for age and education, the linear regression model suggests that bone Al is reflective of 15 years of exposure based off the significant association between bone Al and 15-year CEI (b=0.91, <i>p</i><0.02). Other models with CEI were not statistically significant.</p><p>In Chapter 4, we evaluated the association between bone, CEI and fingernail Al measurements with olfactory and cognitive function. The relationship between cognitive and olfactory function was compared with bone Al (N=43), fingernail Al (FnAl) (N=56), 5 year Al CEI and lifetime Al CEI (N=61) measurements. Olfactory function was assessed with the University of Pennsylvania Smell Identification Test and cognitive function was assessed with the WHO/UCLA Auditory Verbal Learning Test (AVLT). Verbal fluency was assessed using Fruit Naming and Animal Naming. Additional variables were assessed via questionnaire. Linear regression models, adjusted for age, education, current alcohol consumption and current smoking status, showed a significant association between higher BnAl and higher recall on the AVLT interference list (b=0.04, 95% Confidence interval (CI)=0.01, 0.08) and higher 5-year CEI with higher recall on the fifth AVLT trial (b=-0.23, 95% CI=-0.45, -0.01). No significant association between FnAl and lifetime CEI with olfactory and cognitive function was observed. </p><p>In Chapter 5, we explored the potential for interactions of Al with another metal to impact the potential association of Al with cognitive and olfactory function. Interaction models used the natural log of fingernail Al with each of copper (Cu), manganese (Mn), lead (Pb) and zinc (Zn) for the 56 male workers. The linear regression models controlled for age, education current alcohol consumption, current smoking status, and all five fingernail metals. Higher ln(FnMn) was associated with lower recall for several AVLT trials. The interaction term for ln(FnAl) and ln(FnZn) was significantly associated with AVLT Trial 1 (β= 1.99, 95% CI=0.07, 3.93), AVLT Trial 5 (β= 2.71, 95% CI= 0.02, 5.41) and AVLT average (β=2.11, 95% CI=0.01, 4.21). </p>Overall, this research presents valuable information regarding noninvasive, <i>in vivo</i>assessment of BnAl and its relationship with other Al biomarkers and measures of cognitive function. To the best of our knowledge, this is the largest study to use INVAA BnAl measurements to quantify long-term aluminum exposures within an occupational population, the first to compare BnAl with an estimate of cumulative Al exposure. Additionally, we are not aware of prior studies which have examined the interaction of fingernail metals, including Al, with olfactory and cognitive tests. Our results suggest BnAl is significantly associated with the prior 15-years of Al exposure and that IVNAA to assess BnAl can be used in field epidemiology studies. For our study, there was limited evidence of an association of BnAl and 5-year CEI with cognitive function. Most comparisons did not show any evidence of an association of Al with cognitive or olfactory function, but a statistically significant interaction between Al and Zn with some measures of cognitive function was observed. It is recommended that our findings be confirmed with larger studies.

Alzheimer’s disease accounts for up to 80% of the cases of dementia making it the most common type of dementia. As of 2015, 46.8 million people are suffering from Alzheimer’s disease worldwide with an alarming rate of increase in the onset of the disease. Despite the ongoing research, the true cause of Alzheimer’s disease remains unknown. Aluminum is one of the major environmental toxins linked to the etiology of Alzheimer’s disease. A pilot clinical study for non-invasive measurement of bone aluminum was performed at the in vivo neutron activation analysis facility at McMaster University including 15 Alzheimer’s and 15 control subjects. A significant difference in bone aluminum, relative to calcium, was found between the two groups. Multiple methods of analysis were investigated to determine the method with the lowest minimum detection limit. The method of in vivo neutron activation analysis allows for the simultaneous activation of multiple elements. As such, it was possible to measure the magnesium levels, which has been shown to be involved in Alzheimer’s disease, in the study subjects. The results of bone measurements did not show a significant association between bone magnesium levels and Alzheimer’s disease. Moreover, the short-term kinetic behaviours of sodium and chlorine, both essential for the human body, were studied. The outcome of this study revealed an increase in the biological half-lives of sodium and chlorine with age and a higher variability in Alzheimer’s patients compared to control subjects. Finally, bone samples from parenteral nutrition patients were analyzed to determine their aluminum content for comparison and benchmarking purposes. The present results suggest a possible association between bone aluminum and the presence of Alzheimer’s disease. No such association was found for magnesium or the biological half-lives of sodium and chlorine. The technique of in vivo neutron activation analysis was shown to be a promising tool for measuring bone aluminum and magnesium; however, a better detection limit is required to strengthen the current results. / Dissertation / Doctor of Philosophy (PhD) / Alzheimer’s disease is the most common form of dementia. The cause of Alzheimer’s disease is unknown, but both genetic and environmental factors are known to be involved. Different elements have been studied for their possible role in this disease. Aluminum and to a lesser extent magnesium have been linked to the etiology of Alzheimer’s disease. The current thesis presents the results of a clinical study that utilizes the method of in vivo neutron activation analysis to measure aluminum and magnesium in the hand bone of Alzheimer’s disease and control subjects. In vivo neutron activation analysis is a non-invasive method that uses neutrons to activate elements in the human body and measures the radiation emitted. Different methods of analyzing the resulting data were investigated to find the most suitable analysis approach. The biological half-lives of sodium and chlorine were also measured to investigate their short-term kinetic behaviour and pattern with age.