Frontotemporal dementia: neuropil spheroids and presynaptic terminal degeneration.

We compared the neuropathological changes of 6 patients with clinically diagnosed lobar dementia. In the 4 patients with histopathology consistent with frontotemporal dementia (FTD), moderate neuronal loss contrasted with marked cortical and subcortical gliosis. We found silver-positive, carbohydrate-rich, spheroidal enlargements of presynaptic terminals within the neuropil of specific central nervous system regions. The spheroids were immunopositive for the cytoskeletal proteins tau, the high molecular weight neurofilament subunit (NF-H), and beta-tubulin. No abnormal tau phosphorylation and only rare ubiquitin immunoreactivity were detected in these structures. Carbohydrate modifications, including advanced glycation end products within the spheroid matrix, were confirmed by lectin binding, and by anti-pentosidine immunoreactivity, an indicator of oxidative stress. Ultrastructurally, the spheroids consisted of unmyelinated, membrane-enclosed structures filled with randomly arrayed pairs of filaments, approximately 8 to 10 nm in diameter, that were sparsely labeled with antibodies to unmodified tau (T14) and NF-H. Despite clinical overlap, the central nervous systems of our FTD patients are distinguishable from those of other patients with other lobar dementias, including Pick's disease and corticobasal degeneration, by the absence of abnormally phosphorylated neuronal or glial tau inclusions. The neuropil spheroids are dystrophic changes of certain selectively vulnerable presynaptic terminals, suggesting a retrograde degenerative process in FTD.