Author Block:Jillian Brunner^1,2, Rachel Keszycki¹, Caroline Nelson¹, Sandra Weintraub¹, Marek Marsel Mesulam, Professor of Neurology¹, Rudolph Castellani¹, Pouya Jamshidi¹, Changiz Geula¹, Tamar Gefen¹.
¹Mesulam Institute for Cognitive Neurology and Alzheimer's Disease, Northwestern University, Chicago, IL, USA, ²College of Medicine, University of Illinois Chicago, Chicago, IL, USA.

Abstract:
Background: Neuropsychiatric symptoms are common in behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA) due to frontotemporal lobar degeneration with tau pathology (FTLD-tau). In addition to cortical regions, dysfunction in the striatum, a subcortical region, has been implicated in neuropsychiatric symptoms. The objective of this study was to examine the relationship between striatal tau pathology and neuropsychiatric symptoms, representing a target for intervention.
Methods: We identified 16 right-handed participants with autopsy-confirmed FTLD-tau from the Northwestern Alzheimer’s Disease Research Center (NU-ADRC) brain bank (bvFTD: n = 8; PPA: n = 8; 3R tau: n = 8; 4R tau: n = 8). Participants completed annual research visits through the NU-ADRC PPA Research Program or clinical core. Level of neuropsychiatric symptoms was quantified via the Neuropsychiatric Inventory Questionnaire (NPI-Q). For each participant, unilateral anterior striatum was sectioned and immunostained with AT-8 to detect phosphorylated tau, and percent AT8-positive area was quantified in QuPath. We compared regional phosphorylated tau burden in the striatum between tau species (3R, 4R), dementia diagnosis (bvFTD, PPA), and relationship to neuropsychiatric symptoms endorsed at the final visit before death via mixed-effects linear regression.
Results: 3R tau cases showed significantly greater percent area of phosphorylated tau immunopositivity vs. 4R tau cases in the nucleus accumbens (p<0.05), putamen (p<0.05) and caudate (p<0.001). Dementia diagnosis or presence of neuropsychiatric symptoms were not significantly associated with striatal tau burden. However, the ratio of putamen to caudate AT-8 was significantly related to final visit NPI-Q score (p<0.05), such that a greater relative burden of caudate tau was associated with more neuropsychiatric symptoms.
Conclusion: Results suggest a potential contribution of striatal tau burden, particularly in the caudate relative to the putamen, to neuropsychiatric symptoms in bvFTD and PPA due to FTLD-tau. Future analyses focused on how tau influences neuronal integrity and inflammation in this region may yield additional insights into the biological substrates underlying these symptoms.