अल्जाइमर रोग और पार्किंसनिज्म जर्नल

अमूर्त

CSF Biomarkers: Low Amyloid-β _1-42 and BDNF and High IFN γ Differentiate Children Exposed to Mexico City High Air Pollution V Controls. Alzheimer's Disease Uncertainties

Lilian Calderón-Garcidueñas, Chih-kai Chao, Charles Thompson, Joel Rodriguez-Diaz, Maricela Franco-Lira, Partha S. Mukherjee and George Perry

Objective: Long-term exposure to fine particulate matter (PM2.5) and ozone above US EPA standards is associated with increased risk of Alzheimer’s disease (AD). Mexico City Metropolitan Area (MCMA) children have prenatal and lifelong exposures to high PM2.5 and O3. MCMA children and young adults exhibit frontal tau hyperphosphorylation (40%) and amyloid-β diffuse plaques (51%) and a brain imbalance in genes involved in oxidative stress, inflammation, innate and adaptive immune responses. Methods: We measured total tau, tau phosphorylated at threonine 181, amyloid-β1-42 (Fujirebio,US), brain derived neurotrophic factor (BDNF), inflammatory mediators, insulin, and leptin in normal CSF samples from 56 MCMA and 26 control children age 11.9 ± 4.7 years. Results: Aβ 1-42 concentrations were lower in MCMA children (p=0.001) and correlated with cumulative PM2.5 (R2= 0.70). MCMA children had low BDNF (p=0.02) and high IFN-γ (p=0.0003) versus controls. In MCMA children, leptin correlated with insulin and MCP-1 (rs 0.34 and 0.41). Conclusion: Low Aβ1-42 in normal CSF samples from megacity children is a major finding given the interpretation of Aβ 1-42 in the temporal evolution of AD biomarkers. Low CSF Aβ, high IFN γ -detected in early AD and a key neuroinflammatory mediator in AD models-, and low BDNF strongly suggest deleterious CSF changes are evolving in 12 y olds, historically showing deficits in attention and short-term memory, information processing speed and executive function, plus olfactory, auditory and metabolic brain changes. Consideration for a shift in the preclinical AD paradigm is put forward in the setting of severe air pollution exposures. CSF children’s derangements involving Aβ 1-42, BDNF and IFN-γ and the potential discontinuity in the leptin central signaling pathway could be signifying a vicious downward spiral towards AD. We need to aim our efforts to the identification and mitigation of environmental factors influencing Alzheimer’s disease.