Recent advances in Trace Element Research in Health

Introduction • Alzheimer's disease (AD) - the major primary cause of dementia • Mild

• High levels of Cu and Zn were detected inside the senile plaques

• Inorganic copper may be toxic, not organic copper (Brewer, Front. Aging Neurosci.

• “Aluminum hypothesis” proposed in the 1960 s

• Exposure to inorganic mercury, bismuth and silver can lead to AD-like pathology

• Chelation therapy for AD treatment is of great interest (Clioquinol, PBT 2,

Objective • differentiate two groups of MCI patients (with normal and pathological levels of

Methods • CSF protein biomarkers (Aβ 1 -42, ttau, p-tau 181, p-tau 199, p-tau

Results • MCI group with pathological Aβ 1 -42 levels had an increase in

• MCI group with pathological p-tau 181 levels had an increase in cerebrospinal

• MCI group with pathological p-tau 199 levels had an increase in cerebrospinal

• MCI group with pathological p-tau 231 levels had an increase in cerebrospinal

• MCI group with pathological VILIP-1 levels had an increase in cerebrospinal fluid

Conclusions • CSF macro and microelements could potentially improve early AD diagnosis established by

Acknowledgements Croatian Institute for Brain Research Goran Šimić, MD, Ph. D Institute for Medical

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

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

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

• 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

• “Aluminum hypothesis” proposed in the 1960 s

• 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

• Chelation therapy for AD treatment is of great interest (Clioquinol, PBT 2, DFO, silicates) • IMPORTANT: blood-brain barrier becomes more permeable during ageing • The result is the leakage of metals from plasma into the brain tissue

Objective • 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:

Methods • CSF protein biomarkers (Aβ 1 -42, ttau, 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)

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

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

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

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

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

Conclusions • 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

Acknowledgements Croatian Institute for Brain Research Goran Šimić, MD, Ph. D Institute for Medical Research and Occupational Health Jasna Jurasović, Ph. D Tatjana Orct, Ph. D University Hospital Centre Zagreb Fran Borovečki, MD, Ph. D Croatian Science Foundation 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