Proton MR spectroscopy (1H-MR spectroscopy) is a quantitative MR imaging technique often used to complement the sensitivity of conventional MR imaging with specific metabolic information. A key metabolite is the amino acid derivative N-acetylaspartate (NAA), which is almost exclusive to neurons and their processes and is, therefore, an accepted marker of their health and attenuation. Unfortunately, most 1H-MR spectroscopy studies only account for small 1- to 200-cm volumes of interest (VOI), representing less than 20% of the total brain volume. These VOIs have at least 5 additional restrictions: 1) To avoid contamination from subcutaneous and bone marrow lipids, they must be placed away from the skull, thereby missing most of the cortex. 2) They must be image-guided onto MR imaging-visible pathology, subjecting them to the implicit assumption that metabolic changes occur only there. 3) They encounter misregistration errors in serial studies. 4) The time needed to accumulate sufficient signal-intensity quality is often restrictive, and 5) they incur (unknown) T1- and T2-weighting. All these issues are avoided (at the cost of specific localization) by measuring the nonlocalized average NAA concentration over the entire brain. Indeed, whole-brain NAA quantification has been applied to several diffuse neurodegenerative diseases (where specific localization is less important than the total load of the pathology), and the results are presented in this review.