Distinct brain iron profiles associated with logopenic progressive aphasia and posterior cortical atrophy.

Quantitative susceptibility mapping (QSM) can detect iron distribution in the brain by estimating local tissue magnetic susceptibility properties at every voxel. Iron deposition patterns are well studied in typical Alzheimer's disease (tAD), but little is known about these patterns in atypical clinical presentations of AD such as logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA). Seventeen PCA patients and eight LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent MRI that included a five-echo gradient echo sequence for calculation of QSM. Mean QSM signal was extracted from gray and white matter for regions-of-interest across the brain using the Mayo Clinic Adult Lifespan Template. Bayesian hierarchical models were fit per-region and per-hemisphere to compare PCA, LPA, 63 healthy controls, and 20 tAD patients. Strong evidence (posterior probability > 0.99) was observed for greater susceptibility in the middle occipital gyrus and amygdala in both LPA and PCA, and in the right inferior parietal, inferior temporal, and angular gyri in PCA and the caudate and substantia nigra in LPA compared to controls. Moderate evidence for greater susceptibility (posterior probability > 0.90) was also observed in the inferior occipital gyrus, precuneus, putamen and entorhinal cortex in both LPA and PCA, along with superior frontal gyrus in PCA and inferior temporal gyri, insula and basal ganglia in LPA, when compared to controls. Between phenotypic comparisons, LPA had greater susceptibility in the caudate, hippocampus, and posterior cingulate compared to PCA, while PCA showed greater susceptibility in the right superior frontal and middle temporal gyri compared to LPA. Both LPA and PCA showed moderate and strong evidence for greater susceptibility than tAD, particularly in medial and lateral parietal regions, while tAD showed greater susceptibility in the hippocampus and basal ganglia. This study proposes the possibility of unique iron profiles existing between LPA and PCA within cortical and subcortical structures. These changes match well with the disease-related changes of the clinical phenotypes, suggesting that QSM could be an informative candidate marker to study iron deposition in these patients.

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Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Singh, Dr. Arvin, Dr. Cogswell and Peter Martin have no disclosures to report. Dr. Whitwell, Dr. Machulda, Dr. Schwarz and Dr. Josephs reported receiving research funding from the NIH. Dr. Graff-Radford reported receiving research support from the NIH and he also serves as an editorial board member for Neurology. Matthew Senjem reported holding stock in Gilead Sciences, Inc., Inovio Pharmaceuticals, Medtronic, Oncothyreon, Inc., and PAREXEL International. Dr. Jack reported serving on an independent data monitoring board for Roche, has consulted for and served as a speaker for Eisai, and consulted for Biogen, but he receives no personal compensation from any commercial entity. He receives research support from NIH, the GHR foundation and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. Dr. Lowe reported consulting for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., AVID Radiopharmaceuticals, and Merck Research and receiving research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals and the NIH (NIA, NCI). Dr. Peterson reported serving on scientific advisory boards for Elan Pharmaceuticals and GE Healthcare, he receives royalties from publishing mild cognitive impairment (Oxford University Press, 2003) and receives research support from NIH. Dr. Knopman reported serving on the DSMB of the DIAN-TU study, he is a site PI for clinical trials sponsored by Biogen, Lilly and the University of Southern California and is funded by NIH. Dr. Shu reported being an investor in C3T technologies which have been licensed to GE Healthcare by Mayo Clinic..