Yet the degree of neuronal loss in cerebellar structures has been mild to negligible and this may explain why classic cerebellar signs such as ataxia, dysmetria, and nystagmus have not been appreciated or reported. However, the finding of ubiquitin-, ubiquilin-, and p62-positive inclusions in the cerebellum has been present in almost every selleck chemical Gefitinib case in which such immuno-histochemistry has been used. Hence, these cerebellar inclusions are now viewed as a highly sensitive and specific marker for the presence of the C9ORF72 mutation.

The cognitive and behavioral features and their known or presumed neuropathologic substrates are described above in the respective sections, but again, the typical cognitive features (executive dysfunction and word retrieval deficits) likely relate to degeneration in the dorsomedial and dorsolateral frontosubcortical networks, and the typical behavioral features (impaired social cognition, prominent apathy, and so on) likely relate to these and other frontosubcortical networks such as the orbitomedial frontal and anterior cingulate circuits. Furthermore, the von Economo neurons in the anterior cingulate and insular regions have been implicated in impaired social cognition [59-61]. These clinical-topography associations are very plausible when abnormalities on MRI, single-photon emission computed tomography, or PET correspond to the specific features that are present in individual cases. The more challenging circumstance is when obvious cognitive or behavioral changes or both are present and the neuroimaging studies are normal regardless of whether any patient has an obvious neurologic cause or has the less obvious FTD phenocopy syndrome.

Memory impairment is not typical of the bvFTD syndrome but is often present in c9FTD/ALS cases; as discussed above, this could relate to hippocampal sclerosis or a retrieval-based deficit due to frontosubcortical dysfunction. Also, even when hippocampal sclerosis is not present, an encoding deficit could relate to dysfunction associated with ubiquitin-, ubiquilin-, Dacomitinib and p62-positive inclusions in the hippocampus [53]. 17-DMAG order Dysfunction associated with these inclusions in the cerebellum as part of the cerebellar cognitive affective syndrome is also possible. This will be challenging to prove or disprove until radioligands that tag these key proteins are available for functional neuroimaging studies [47]. Summary A summary of the salient features of the FTD-predominant phenotype of c9FTD/ALS due to the GGGGCC hexanucleotide repeat expansion in C9ORF72 is presented in Table ?Table33.