A Critical Proton MR Spectroscopy Marker of Alzheimer’s Disease Early Neurodegenerative Change: Low Hippocampal NAA/Cr Ratio Impacts APOE ɛ4 Mexico City Children and Their Parents

Article type: Research Article

Authors: Calderón-Garcidueñas, Lilian^{a; b; *} | Mora-Tiscareño, Antonieta^c | Melo-Sánchez, Gastón^b | Rodríguez-Díaz, Joel^d | Torres-Jardón, Ricardo^e | Styner, Martin^f | Mukherjee, Partha S.^g | Lin, Weili^h | Jewells, Valerie^h

Affiliations: [a] The Center for Structural and Functional Neurosciences, The University of Montana, Missoula, MT, USA | [b] Escuela de Ciencias de la Salud, Universidad del Valle de México, Campus Saltillo, Saltillo, Coahuila, México | [c] Instituto Nacional de Pediatría, Mexico City, México | [d] Centro Médico Cozumel, Cozumel, Quintana Roo, México | [e] Centro de Ciencias de la Atmósfera, Universidad Nacional Autónoma de México, Mexico City, Mexico | [f] Department of Psychiatry and Computer Science, University of North Carolina, Chapel Hill, NC, USA | [g] Mathematics Department, Boise State University, Boise, ID, USA | [h] Neuroradiology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

Correspondence: [*] Correspondence to: Lilian Calderón-Garcidueñas, MD, PhD, The Center for Structural and Functional Neurosciences, University of Montana, 32 Campus Drive, 287 Skaggs Building, Missoula, MT 59812, USA. Tel.: +l 406 243 4785; Fax: +1 406 243 5228; [email protected]

Abstract: Severe air pollution exposures produce systemic, respiratory, myocardial, and brain inflammation and Alzheimer’s disease (AD) hallmarks in clinically healthy children. We tested whether hippocampal metabolite ratios are associated with contrasting levels of air pollution, APOE, and body mass index (BMI) in paired healthy children and one parent sharing the same APOE alleles. We used 1H-MRS to interrogate bilateral hippocampal single-voxel in 57 children (12.45 ± 3.4 years) and their 48 parents (37.5 ± 6.78 years) from a low pollution city versus Mexico City (MC). NAA/Cr, Cho/Cr, and mI/Cr metabolite ratios were analyzed. The right hippocampus NAA/Cr ratio was significantly different between cohorts (p = 0.007). The NAA/Cr ratio in right hippocampus in controls versus APOE ɛ4 MC children and in left hippocampus in MC APOE ɛ4 parents versus their children was significantly different after adjusting for age, gender, and BMI (p = 0.027 and 0.01, respectively). The NAA/Cr ratio is considered reflective of neuronal density/functional integrity/loss of synapses/higher pTau burden, thus a significant decrease in hippocampal NAA/Cr ratios may constitute a spectral marker of early neurodegeneration in young urbanites. Decreases in NAA/Cr correlate well with cognitive function, behavioral symptoms, and dementia severity; thus, since the progression of AD starts decades before clinical diagnosis, our findings support the hypothesis that under chronic exposures to fine particulate matter and ozone above the standards, neurodegenerative processes start in childhood and APOE ɛ4 carriers are at higher risk. Gene and environmental factors are critical in the development of AD and the identification and neuroprotection of young urbanites at high risk must become a public health priority.

Keywords: Air Pollution, APOE, body mass index, children, hippocampus, magnetic resonance spectroscopy, memory, NAA/Cr ratio, neuroprotection, PM_2.5

DOI: 10.3233/JAD-150415

Journal: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 1065-1075, 2015