Cerebrospinal Fluid Biomarkers in Highly Exposed PM_2.5 Urbanites: The Risk of Alzheimer’s and Parkinson’s Diseases in Young Mexico City Residents

Article type: Research Article

Authors: Calderón-Garcidueñas, Lilian^{a; b; *} | Avila-Ramírez, José^c | Calderón-Garcidueñas, Ana^d | González-Heredia, Tonatiuh^b | Acuña-Ayala, Hilda^b | Chao, Chih-kai^a | Thompson, Charles^a | Ruiz-Ramos, Rubén^d | Cortés-González, Victor^e | Martínez-Martínez, Luz^e | García-Pérez, Mario Alberto^f | Reis, Jacques^g | Mukherjee, Partha S.^h | Torres-Jardón, Ricardoⁱ | Lachmann, Ingolf^j

Affiliations: [a] The University of Montana, Missoula, MT, USA | [b] Universidad del Valle de México, México | [c] Médica Sur, Mexico City, México | [d] Instituto de Medicina Forense, Universidad Veracruzana, Boca del Río, México | [e] Hospital de Especialidades No. 14, I.M.S.S, Boca del Río, México | [f] Hospital Regional de Alta Especialidad, Ciudad Victoria, Tamaulipas, México | [g] Service de Neurologie, Centre Hospitalier Universitaire, Hôpital de Hautepierre, Strasbourg, France | [h] Mathematics Department, Boise State University, Boise, ID, USA | [i] Universidad Nacional Autónoma de México, Mexico City, México | [j] AJ Roboscreen GmbH, Leipzig, Germany

Correspondence: [*] Correspondence to: Lilian Calderón-Garcidueñas MA, MD, PhD, University of Montana, 32 Campus Drive, 287 Skaggs Building, Missoula, MT 59812, USA. Tel.: +1 406 243 4785; Fax: +1 406 243 5228; E-mail: [email protected].

Abstract: Exposure to fine particulate matter (PM2.5) and ozone (O3) above US EPA standards is associated with Alzheimer’s disease (AD) risk, while Mn toxicity induces parkinsonism. Mexico City Metropolitan Area (MCMA) children have pre- and postnatal sustained and high exposures to PM2.5, O3, polycyclic aromatic hydrocarbons, and metals. Young MCMA residents exhibit frontal tau hyperphosphorylation and amyloid-β (Aβ)1 - 42 diffuse plaques, and aggregated and hyperphosphorylated α-synuclein in olfactory nerves and key brainstem nuclei. We measured total prion protein (TPrP), total tau (T-tau), tau phosphorylated at threonine 181 (P-Tau), Aβ1–42, α-synuclein (t-α-syn and d-α-synuclein), BDNF, insulin, leptin, and/or inflammatory mediators, in 129 normal CSF samples from MCMA and clean air controls. Aβ1–42 and BDNF concentrations were significantly lower in MCMA children versus controls (p = 0.005 and 0.02, respectively). TPrP increased with cumulative PM2.5 up to 5 μg/m3 and then decreased, regardless of cumulative value or age (R2 = 0.56). TPrP strongly correlated with T-Tau and P-Tau, while d-α-synuclein showed a significant correlation with TNFα, IL10, and IL6 in MCMA children. Total synuclein showed an increment in childhood years related to cumulated PM2.5, followed by a decrease after age 12 years (R2 = 0.47), while d-α-synuclein exhibited a tendency to increase with cumulated PM2.5 (R2 = 0.30). CSF Aβ1–42, BDNF, α-synuclein, and TPrP changes are evolving in young MCMA urbanites historically showing underperformance in cognitive processes, odor identification deficits, downregulation of frontal cellular PrP, and neuropathological AD and PD hallmarks. Neuroprotection of young MCMA residents ought to be a public health priority.

Keywords: Air pollution, Alzheimer’s disease, amyloid-β_1–42, α-synuclein, BDNF, children, cerebrospinal fluid, insulin, leptin, Mexico City, prion cellular protein, PM_2.5, Parkinson

DOI: 10.3233/JAD-160472

Journal: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 597-613, 2016