Whether VENs and fork cells are prone to tau accumulation in FTLD-tau remains unclear, and no previous studies of these neurons have focused on patients with pathogenic variants in the gene encoding microtubule-associated protein tau (FTLD-tau/and 7 with Picks disease (PiD), a sporadic form of FTLD-tau that often presents with bvFTD

Whether VENs and fork cells are prone to tau accumulation in FTLD-tau remains unclear, and no previous studies of these neurons have focused on patients with pathogenic variants in the gene encoding microtubule-associated protein tau (FTLD-tau/and 7 with Picks disease (PiD), a sporadic form of FTLD-tau that often presents with bvFTD. Picks disease (PiD), a sporadic form of FTLD-tau that often presents with bvFTD. We further qualitatively assessed the cellular patterns of frontoinsular tau aggregation in FTLD-tau/using antibodies specific for tau hyperphosphorylation, acetylation, or conformational change. ACC and mid-insula were among the regions most affected by neurodegeneration and tau aggregation in FTLD-tau/and PiD. In these two forms of FTLD-tau, severity of regional neurodegeneration and tau protein aggregation were highly correlated across regions. In FTLD-tau/variants we studied. [13C15], we reasoned that an assessment of VEN and fork cell vulnerability in this patient group could provide an important backdrop for RBX1 the field. We hypothesized that ACC and FI VENs and fork cells are prone to tau aggregation in FTLD-tau, as they are to TDP-43 aggregation in FTLD-TDP. Here, we combined a semi-quantitative regional analysis with a qualitative assessment of neuron type-specific aggregation of tau in ACC and FI. Forty brain regions were prospectively rated for neurodegeneration and tau inclusions in 8 patients with FTLD-tau/and 7 with sporadic bvFTD-PiD. We then focused on tau aggregation within VENs, fork cells, and neighboring neurons in patients with FTLD-tau/representing four variants from different exons, introns, and families (V337?M: exon 12 mutation; P301L: exon 10 mutation; IVS10?+?16: intron 10 mutation; A152T: risk variant), using monoclonal antibodies labeling tau acetylation, hyperphosphorylation, and conformational changes. The findings suggest overlapping regional and neuron type-specific vulnerability in sporadic and inherited FTLD-tau. Gimeracil Material and methods Patients and autopsy procedures Post-mortem human brain tissue was obtained from the UCSF Neurodegenerative Disease Brain Bank. Clinical diagnoses of bvFTD, non-fluent variant primary progressive aphasia (nfvPPA), and progressive supranuclear palsy-Richardson syndrome (PSP-RS), were made according to prevailing international consensus criteria at the time of assessment [16, 17]. Neuropathological diagnoses were made following consensus diagnostic criteria using previously described histological and immunohistochemical methods [18C20]. Cases were selected based on clinical and neuropathological diagnoses, and genetic analysis [7, 21] (Table?1 Additional file 1: Table S1). Initial brain cutting and processing depended on the site of brain procurement. For Cases 1C4, 6C8 of FTLD-tau/group with Case 3 of PiD group, one cerebral hemisphere was immersion fixed in 10% buffered formalin indefinitely. The remaining cases were cut freshly into ~?1?cm-thick coronal slabs and fixed in 10% neutral buffered formalin for ~?72?h. The FTLD-tau/cohort (was compared to sporadic bvFTD due to PiD (variantand FTLD-PiD. We employed a and PiD share prominent involvement of ACC and mid-insular cortex To evaluate how our patients with FTLD-tau/((r?=?0.74, and PiD reached a plateau in the presence of severe neurodegeneration. As in Gimeracil PiD, in FTLD-tau/the ACC subregions and insula were among the Gimeracil ten most affected regions, based on the regional composite scores (Fig. ?(Fig.1b).1b). In addition to ACC and middle insula, amygdala and PAG, also nodes within the salience network, were among the 10 most affected regions in FTLD-tau/were included in the top 10 10 for PiD. Overall, the FTLD-tau/cases had a similar ranking of regional burden to the PiD casesP301L cases showed the most severe tau burden, with relatively high composite scores across most regions, including those in the salience network, followed by IVS10?+?16 cases, then V337?M. As expected, the A152T case with underlying PSP, which primarily affects subcortical and brainstem structures, showed the mildest tau deposition in cortical regions. Open in a separate window Fig. 1 a Correlation of neurodegeneration and tau pathology in the FTLD-tau/and PiD cases across regions. b Ten most affected regions in the FTLD-tau/cases showed similar ranking of regional burden as PiD cases. The insular and cingulate cortex are highlighted.