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Objective MPS IIIA is a progressive neurological disease. Quantitative MRI and neurocognitive function testing may provide understanding of MPS IIIA disease progression. From the natural history of MPS IIIA (NCT01047306), we previously reported that baseline cognition is significantly associated with age and gray matter volumes. Here, we present longitudinal data regarding regional changes in MRI-measured brain volumes in MPS IIIA patients, and estimates of the rate of decline in both cognition and brain volumes over 24 months. Methods Longitudinal cognitive and quantitative MRI data were collected from 24 children with documented MPS IIIA. Brain volumetric analysis and developmental quotient (DQ) were obtained by automated MRI segmentation and cognitive assessment, respectively. Results For a subset of 19 patients with classic disease diagnosed prior to age six, volume decreases were noted in cortex (-7.5%/year)*, amygdalae (-15%/year)*, hippocampi (-4.9%/year)*, and very slightly in white matter (-2.2%/year). Cortical thickness narrowed with a rate of 5.9% per year*. Subcortical gray matter and cortical cerebellar volumes remained stable. Ventricular volume increased (+23.5%/year)*, presumably reflecting the brain loss. A strong correlation was found between DQ and cortical volume and similarly between DQ and cortical thickness. Other specific data will be reported (e.g., rate of decline for individual lobes of the brain). For patients diagnosed after age six, patterns were variable. *p Conclusion In this natural history study, loss of cortical and amygdalar volumes with substantial ventricular enlargement were the primary MRI patterns linked to decline in cognitive function in patients with the classical form of MPS IIIA. We have demonstrated that both DQ and Cortical Volume are markers of disease progression in MPS IIIA, and that they are closely associated. White matter, cerebellum and subcortical gray matter remained stable or declined slightly. MPS IIIA appears to be mainly a disease of cerebral cortical gray matter.