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Background: Neurodegenerative pathologies, including tau depositions, have been implicated in late‐onset depression (LOD), while there is a lack of in‐vivo evidence for the neuropathological basis of late‐onset bipolar disorder (LOBD) despite postmortem findings of cerebral tau accumulations. The current study aimed to assess tau pathologies in LOBD and LOD patients positron emission tomography (PET) with 18F‐florzolotau, a radioligand for Alzheimer's disease (AD) and non‐AD tau fibrils. Methods: We studied LOBD and LOD patients who developed the first episode of mania or depression after age 45. Twenty‐one patients with LOBD (68.8 ± 9.6 years old; 11 females), 15 patients with LOD (73.0 ± 5.8 years old; 11 females), and 39 age‐matched healthy controls (HCs) (67.1 ± 9.1 years old; 19 females) underwent tau and amyloid PET scans with 18F‐florzolotau and 11C‐PiB, respectively. Amyloid positivity was determined by a visual read of 11C‐PiB‐PET images, and tau depositions were assessed by calculating standardized uptake value ratios (SUVRs) in 52 regions covering the cerebral grey matter and basal ganglia to the optimized reference tissue. All SUVRs were corrected for age and sex and converted to Z‐score relative to HCs. The positivity and topology of tau pathologies were determined according to the presence of a region with a Z‐score ≥ 2.0. Results: 18F‐florzolotau‐PET positivity was observed in 13 LOBD (62%), 7 LOD (47%), and 11 HC (28%) subjects, whereas 4 LOBD, 4 LOD, and no HC individuals were 11C‐PiB‐PET‐positive. A significant difference in the prevalence of tau pathologies was only found between LOBD and HCs (P = 0.043, corrected for multiple comparisons). Tau topologies in the cases with 11C‐PiB‐PET‐positive AD pathologies consisted of predominant frontal (1 LOBD and 3 LODs), lateral temporal (3 LOBDs and 1 LOD), and posterior (1 LOBD) accumulations. Meanwhile, tau pathologies in 11C‐PiB‐negative cases showed predominant frontal (2 LOBDs and 1 LOD), temporal (1 LOBD and 1 LOD), posterior (4 LOBDs and 1 LOD), and basal ganglia (2 LOBDs) localizations. Conclusion: Our findings suggest that a significant subset of LOBD patients harbor tau lesions linked to various AD subtypes and non‐AD tauopathies indicative of distinct early‐stage frontotemporal lobar degeneration subcategories. [ABSTRACT FROM AUTHOR]

Background: Several blood‐based phosphorylated tau (p‐tau) assays that focus on the N‐terminus have been developed and established as non‐invasive biomarkers for detecting Alzheimer's disease (AD) pathologies from their early stages. However, the p‐tau measured by these assays may not necessarily reflect the accumulation of tau lesions in the brain due to correlation with Aβ burden. Therefore, there remains a significant unmet need to develop blood‐based tau biomarkers that are interchangeable with tau deposits in the brain. Methods: We have devised a novel Simoa assay that can detect N‐ and C‐terminally truncated fragment of p‐tau181 in plasma (QST assay), utilizing an antibody against the mid‐region of tau protein for capture, and an antibody AT270 for detection. The plasma p‐tau181 was measured with both the QST assay and a conventional p‐tau181 Simoa assay (Quanterix) in 164 subjects, including 40 cognitively normal (CN) individuals, 48 with AD continuum, 50 with progressive supranuclear palsy, and 26 with other frontotemporal lobar degeneration, who underwent Aβ (11C‐PiB) and tau (18F‐PM‐PBB3, Florzorotau) positron emission tomography (PET) scans. Subsequently, we conducted a head‐to‐head comparison of p‐tau181 assays in correlation with the imaging biomarker and cognitive dysfunction. Results: QST p‐tau assay demonstrated inferior performance compared to the Quanterix assay in the qualification of Aβ PET (QST assay: AUC = 0.771, Quanterix assay: AUC = 0.867). Neither assay showed a significant correlation with Aβ PET accumulation in the AD group. Meanwhile, the QST assay exhibited excellent correlations with tau PET accumulation in regions indicative of AD including temporal cortex and neocortex (p<0.0005), whereas the Quanterix assay demonstrated non‐linear correlations with tracer binding. In trajectories from CN to AD continuum, the QST assay exhibited a linear association, as well as tau PET accumulation, while the Quanterix assay exhibited a sigmoidal curve association. Conclusions: We have developed a new p‐tau181 assay directly correlated with tau PET accumulation. This quantitative system serves as a promising surrogate marker for tau lesions in the AD brain, which facilitate screening and monitoring of tau deposits in various settings, including developing disease‐modifying therapeutics. [ABSTRACT FROM AUTHOR]