1. Recent advances in Trace Element Research in Health and Disease Dubrovnik, 18-22 Oct 2015 Mirjana Babić Leko, mag.biol.mol Department of Neuroscience Croatian Institute for Brain Research University of Zagreb Medical School, Zagreb, Croatia Macro and microelements as biomarkers of mild cognitive impairment

2. Introduction Alzheimer's disease (AD) - the major primary cause of dementia Mild cognitive impairment (MCI) is a syndrome characterized by cognitive impairment without dementia About 10% MCI patients convert to AD annually FDG-PET

3. Andreasson et al., 2007. High levels of Cu and Zn were detected inside the senile plaques Fe accumulated intraneuronally Campbell-Switzer-Martin's method

4. Inorganic copper may be toxic, not organic copper (Brewer, Front. Aging Neurosci., 2014) environmental source of inorganic copper: - leaching of copper from copper plumbing - pills containing copper Zn deficiency is the risk factor for Alzheimer's disease

5. “Aluminum hypothesis” proposed in the 1960s

6. Exposure to inorganic mercury, bismuth and silver can lead to AD-like pathology in noradrenergic locus coeruleus neurons spreads to neighbouring serotonergic dorsal raphe neurons (Pamphlett and Kum Jew, JAD, 2015) Hg affects the metabolism of amyloid β and tau protein locus coeruleus neurons

7. Chelation therapy for AD treatment is of great interest (Clioquinol, PBT2, DFO, silicates) IMPORTANT: blood-brain barrier becomes more permeable during ageing The result is the leakage of metals from plasma into the brain tissue

8. differentiate two groups of MCI patients (with normal and pathological levels of Alzheimer's disease protein biomarkers) using 24 macro and microelements measured in cerebrospinal fluid: Objective

9. CSF protein biomarkers (Aβ 1-42, t- tau, p-tau 181, p-tau 199, p-tau 231 and VILIP-1) measured using ELISA ( Laboratory for Developmental Neuropathology ) CSF macro and microelements measured using inductively coupled plasma mass spectroscopy (ICP-MS) ( Institute for Medical Research and Occupational Health ) Methods

10. MCI group with pathological Aβ 1-42 levels had an increase in cerebrospinal fluid levels of: Results

11. MCI group with pathological p-tau 181 levels had an increase in cerebrospinal fluid levels of:

12. MCI group with pathological p-tau 199 levels had an increase in cerebrospinal fluid levels of:

13. MCI group with pathological p-tau 231 levels had an increase in cerebrospinal fluid levels of:

14. MCI group with pathological VILIP-1 levels had an increase in cerebrospinal fluid levels of:

15. CSF macro and microelements could potentially improve early AD diagnosis established by protein biomarkers The most promising CSF macro and microelements as biomarkers – Hg, K, Cr, Fe, S, Cu, As and Se Results should be validated in bigger group of patients and compared to the levels of macro and microelements in plasma Conclusions

16. Funded by: Croatian Science Foundation project IP-2014-09-9730 “Tau protein hyperphosphorylation, aggregation and trans-synaptic transfer in Alzheimer's disease: cerebrospinal fluid analysis and assessment of potential neuroprotective compounds“ http://alztauprotect.hiim.hr Croatian Science Foundation Acknowledgements Croatian Institute for Brain Research Goran Šimić, MD, PhD Institute for Medical Research and Occupational Health Jasna Jurasović, PhD Tatjana Orct, PhD University Hospital Centre Zagreb Fran Borovečki, MD, PhD