When I say … Simulated 'patients'.

Alzheimer disease (AD) neuropathologic change (ADNPC), Parkinson disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS) are defined by their biology and neuropathology. ADNPC, PD, FTLD, and/or ALS exist in a continuum and they overlap. Overlapping neuropathology is a major driver of heterogeneity in the clinical presentation and extent of neurodegeneration in AD patients. The description of AD hallmarks in children is not new; Braak et al described them in 2011. We have reported the development of AD, PD, FTLD, and ALS neuropathology in Metropolitan Mexico City (MMC) pediatric and young adult forensic autopsies and emphasized that their early neuropathology overlap is not different from that of US elderly cognitively unimpaired and impaired subjects. Moreover, the neuropathologic burden leads to the appearance and progression of impairment of cognitive function, (along with cortical first parietal and fronto-parietal, precentral gyrus, hippocampi, basal ganglia, thalamus, amygdala and cerebellar atrophy), and disturbances of olfaction, audition, sleep, gait and balance in the absence of comorbidities or known risk factors. MMC children exhibit more numerous MRI white matter hyperintense lesions with enlargement of perivascular spaces, spectroscopic abnormal brain metabolites, low CSF concentrations of Aβ and brain-derived neurotrophic factor than low pollution controls. We have identified ADNPC, hyperphosphorylated tau Braak staging acceleration, a high risk of suicide and IQ decreases if they carry one Apolipoprotein E 4 allele. Pathophysiologic mechanisms involved very early in the disease processes include damage to the neurovascular unit, oxidative stress and neuroinflammation correlating with PM, ultrafine particulate matter (UFPM) and magnetic nanoparticle (NP) exposure. MMC is a megacity with unrestrained urban growth and complex, severe environmental pollution. Key to this work is the NP distribution in MMC: Caudillo et al described three NPs primary emission modes during morning peak traffic hours along a secondary mode coinciding with the highest photochemical activity. MMC residents walking along high traffic avenues are exposed to NPs 49 ± 20 nm, composed of ∼60% Fe, Pb, and Zn. The MMC subway represents a serious health hazard with PM exposures 34 to 93 μg/m, including NP number concentrations up to 50 300 ± 10 600 (# cm) with an average size of 38 ± 16 nm, predominantly composed of Fe, Cu, Ni, Cr, and Mn.