Brain total creatine differs between primary progressive aphasia (PPA) subtypes and correlates with disease severity

Background: Primary progressive aphasia (PPA) is a debilitating neurodegenerative disease that primarily impairs language function. It is comprised of three subtypes with varied clinical presentation and cortical atrophy patterns: logopenic variant (lvPPA), non-fluent variant (nfvPPA), and semantic variant (svPPA). No prior work has examined differences in brain chemistry between the PPA subtypes, or associations of brain chemistry with symptom severity. Methods: We collected magnetic resonance spectroscopy (MRS) data in the left inferior frontal gyrus (IFG, a main language production region) and the right sensorimotor cortex (SMC) from 61 PPA patients. We analyzed tissue-corrected metabolite levels to account for the effects of cortical atrophy and other tissue-specific properties. We aimed to: 1) characterize differences between PPA subtypes for 5 brain metabolites: total N-acetylaspartate (tNAA), total choline (tCho), total creatine (tCr), glutamate+glutamine (Glx), and gamma-aminobutyric acid (GABA); and 2) test for associations between these neurometabolites and PPA symptom severity. Results: tCr levels differed by PPA subtype across both the left IFG and right SMC. In both regions, tCr levels were lowest among lvPPA patients and highest among svPPA patients. Moreover, across the whole cohort, higher tCr and lower Glx levels in the left IFG correlated with greater disease severity. Conclusions: Given that tCr is involved in brain energy metabolism and homeostasis, our results indicate that svPPA pathology might involve changes in specific cellular energy processes. Moreover, our finding that higher tCr was associated with worse PPA symptom severity suggests that perturbations to cellular energy homeostasis in cortical language areas may contribute to PPA symptoms. In addition, reduced cortical excitatory capacity (i.e., lower Glx) in brain areas related to language processing may also contribute to PPA symptoms. Together, these findings suggest that tCr could serve as a biomarker to differentiate between PPA subtypes, and that both tCr and Glx might have utility for better understanding PPA disease mechanisms and tracking disease progression. Trial registration: ClinicalTrials.gov (NCT02606422). Registered 11 November 2015 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02606422?term=NCT02606422&draw=2&rank=1