TDP-43 and FUS normal cytoplasmic functions are thought to involve regulated aggregation and disaggregation [1, 5, 8], similar to that of prion proteins, where aggregation occurs by a self-templating process, likely involving properties of amyloid, or beta-pleated sheet structure. Both thioflavin-T and thioflavin-S fluoresce when bound to amyloid fibrils [7]. We previously showed that TDP-43 peptides form amyloidogenic fibrils, binding to thioflavin-T [3]. Recently, TDP-43-positive lower motor neuron (LMN) inclusions in 28% of 47 cases of ALS, but no inclusions in 22 FTLD-TDP cases, were shown to be positive with thioflavin-S [6]. Using thioflavin-S, we surveyed brain tissues from 44 cases, including FTLD-TDP type A (17 cases), type B (14 cases), type C (3 cases), sporadic ALS (2 cases), familial ALS (FALS)(2 each with SOD1 and C9orf72 mutations), and FTLD-FUS, including atypical FTLD-U (aFTLD-U, 2 cases) and basophilic inclusion body disease (BIBD, 2 cases). Our routine modified thioflavin-S stain includes pretreatment of tissue sections with potassium permanganate and bleaching with potassium metabisulfite and oxalic acid followed by treatment with sodium hydroxide and hydrogen peroxide, removing lipid autofluorescence and resulting in improved definition of pathological lesions. Slides were viewed using a Nikon BV-2A filter cube. Confocal microscopy was performed using thioflavin-S staining as above and phospho TDP43 (pS409/410-1). Inclusions in most cases of FTLDTDP and ALS were thioflavin-S positive. The density and distribution of thioflavin-S positive inclusions was similar to that seen with ubiquitin and fewer than with TDP-43 immunohistochemistry. In FTLD-TDP type A, neuronal intranuclear inclusions (NIIs), neuronal cytoplasmic inclusions (NCIs) and dystrophic neurites (DNs) were strongly fluorescent (Fig. 1 a). Fluorescent confocal microscopy showed co-localization of thioflavin-S with TDP-43 positive inclusions (Fig. 1 b). In FTLD-TDP type B, rare NCIs in all layers of cortex were positive, but dentate gyrus inclusions were easily seen (Fig. 1 c). In FTLD-TDP type C, long DNs in cortex were strongly thioflavin-S positive (Fig. 1 d). Inclusions in FTLD-FUS were negative with thioflavin-S; while rare hippocampal dentate gyrus neurons had fluorescent granular inclusions, large cytoplasmic inclusions and intranuclear vermiform inclusions were not seen with thioflavin-S (Fig. 2). Skein-like inclusions (SLI) and Lewy-like bodies (LLB) in LMNs of ALS cases were positive with thioflavin-S (Fig. 3). The two cases of FALS with SOD1 mutations were not thioflavin-S positive. Additionally, eight of the 17 cases of FTLD-TDP type A had exuberant