Studies of neurodegenerative diseases, such as Alzheimer’s disease (AD), have sometimes produced contradictory data about the role of metals in disease progression. New research by NIEHS scientists and colleagues at Duke University moved a step closer to explaining those contradictions by showing that levels of metals in ventricular fluid (VF) do not represent levels in tissue from the frontal cortex. The researchers also confirmed higher levels of iron in the brain tissue of patients with Alzheimer’s disease.
The team included Jean Harry, Ph.D., head of the National Toxicology Program (NTP) Neurotoxicology Group, and Linda Birnbaum, Ph.D., director of NIEHS and NTP. They published their research in the April issue of the journal Toxicological Sciences.
The scientists analyzed postmortem samples from Alzheimer’s disease cases and individuals without the disease, with an average age of 88 years old. Levels of 13 metals were determined in samples from the central nervous system, including the frontal cortex and the ventricular fluid. Harry pointed out that they looked for metals essential to body processes, such as iron and zinc, as well as environmental metals, including arsenic and lead.
Ventricular fluid is not a surrogate for brain tissue
Importantly, the scientists compared the metals levels observed in ventricular fluid with those in the frontal cortex, for both groups of individuals. “We found that the ability to predict brain levels from VF levels was marginal,” they wrote. Some metals present in brain tissue were not detected in the fluid.
“Our findings are an important reminder that we cannot look at the VF and tell what is happening in a target tissue such as the brain,” Birnbaum said, pointing out the need to learn more about differences in how fluids and tissues handle metals. “Analyzing samples of brain, ventricular fluid, and blood may help define what is relevant for studies of metals and neurodegenerative disease," she said.
Moreover, the authors suggested that the variable results reported by other studies may be due to important differences among the tissues and fluids tested, as well as the test methods used.
Key findings on iron and zinc
“Iron levels were significantly higher in AD cases,” Harry said. “That’s the only metal analyzed that we can clearly make that statement for.” She said that this finding is consistent with scientific opinion that Alzheimer’s patients may demonstrate elevated iron levels in the brain.
Harry highlighted the absence of an association with zinc levels as an interesting finding, because previous studies have suggested a link with Alzheimer’s disease.
Taken together, the results led the scientists to question whether essential metal overload was important in the progression of neurodegenerative disease, as some researchers suspect.
Cautions and next steps
The authors cautioned that samples were analyzed for total metals, and they suggested that testing for particular forms of a metal might produce different results. Similarly, the team did not rule out the possibility that metals levels in specific brain regions, such as the hippocampus, or in certain types of cells, including microglia, might differ from those in the frontal cortex.
In addition, according to Harry, the new data provide insights about human exposure because of the detectable levels of environmental metals found in human brain tissue.
"Follow-up studies will examine brain tissue levels of various persistent organic pollutants that may also provide us with information on human exposure," Harry said.
Citation: Szabo ST, Harry GJ, Hayden KM, Szabo DT, Birnbaum L. 2016. Comparison of metal levels between postmortem brain and ventricular fluid in Alzheimer's disease and nondemented elderly controls. Toxicol Sci. 150:292-300.