Brain imaging can reveal specific characteristics of Cognitive Impairment (CI) related to neurotoxicant exposure. Unique brain characteristic patterns of CI have been revealed among World Trade Center (WTC) responders to the 9/11 terrorist attack, compared to other signatures, including Alzheimer's Disease (AD). Diffuse brain atrophy, reduced cortical thickness and hippocampal subfield volume analyses suggest that reductions in specific subregions are specifically associated with the duration of WTC exposure. These findings support the hypothesis that WTC exposure to neurotoxicants and intense psychological trauma are causing long-term neurodegenerative impacts. The neuro-phenotype of this impairment is distinct from the AD and inconsistent with signatures developed for other known neurodegenerative diseases. The World Trade Center Cognitive Impairment (WTC-CI) may be a WTC-specific encephalopathy with an unknown etiology characterized by widespread cortical atrophy. Applying similar brain imaging modalities, a diffuse brain deposition of fibrillar amyloid-β (Aβ) peptide was observed among ferroalloy workers with prolonged occupational exposure to manganese. These two case studies provide further evidence of how modern brain imaging can improve understanding of relevant mechanisms of neurotoxicity after long term exposure to neurotoxicants.