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The middle longitudinal fascicle (MdLF) is a recently delineated association cortico-cortical fiber pathway in humans, connecting superior temporal gyrus and temporal pole principally with the angular gyrus, and is likely to be involved in language processing. However, the MdLF has not been studied in language disorders as primary progressive aphasia (PPA). We hypothesized that the MdLF will exhibit evidence of neurodegeneration in PPA patients. In this study, 20 PPA patients and 25 healthy controls were recruited in the Primary Progressive Aphasia program in the Massachusetts General Hospital Frontotemporal Disorders Unit. We used diffusion tensor imaging (DTI) tractography to reconstruct the MdLF and extract tract-specific DTI metrics (fractional anisotropy (FA), radial diffusivity (RD), mean diffusivity (MD) and axial diffusivity (AD)) to assess white matter changes in PPA and their relationship with language impairments. We found severe WM damage in the MdLF in PPA patients, which was principally pronounced in the left hemisphere. Moreover, the WM alterations in the MdLF in the dominant hemisphere were significantly correlated with impairments in word comprehension and naming, but not with articulation and fluency. In addition, asymmetry analysis revealed that the DTI metrics of controls were similar for each hemisphere, whereas PPA patients had clear laterality differences in MD, AD and RD. These findings add new insight into the localization and severity of white matter fiber bundle neurodegeneration in PPA, and provide evidence that degeneration of the MdLF contribute to impairment in semantic processing and lexical retrieval in PPA., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Recent studies have shown that positron emission tomography (PET) tracer AV-1451 exhibits high binding affinity for paired helical filament (PHF)-tau pathology in Alzheimer's brains. However, the ability of this ligand to bind to tau lesions in other tauopathies remains controversial. Our goal was to examine the correlation of in vivo and postmortem AV-1451 binding patterns in three autopsy-confirmed non-Alzheimer tauopathy cases., Methods: We quantified in vivo retention of [F-18]-AV-1451 and performed autoradiography, [H-3]-AV-1451 binding assays, and quantitative tau measurements in postmortem brain samples from two progressive supranuclear palsy (PSP) cases and a MAPT P301L mutation carrier. They all underwent [F-18]-AV-1451 PET imaging before death., Results: The three subjects exhibited [F-18]-AV-1451 in vivo retention predominantly in basal ganglia and midbrain. Neuropathological examination confirmed the PSP diagnosis in the first two subjects; the MAPT P301L mutation carrier had an atypical tauopathy characterized by grain-like tau-containing neurites in gray and white matter with heaviest burden in basal ganglia. In all three cases, autoradiography failed to show detectable [F-18]-AV-1451 binding in multiple brain regions examined, with the exception of entorhinal cortex (reflecting incidental age-related neurofibrillary tangles) and neuromelanin-containing neurons in the substantia nigra (off-target binding). The lack of a consistent significant correlation between in vivo [F-18]-AV-1541 retention and postmortem in vitro binding and tau measures in these cases suggests that this ligand has low affinity for tau lesions primarily made of straight tau filaments., Interpretation: AV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in these non-Alzheimer tauopathies. ANN NEUROL 2017;81:117-128., (© 2016 American Neurological Association.)