eprintid: 10143513 rev_number: 9 eprint_status: archive userid: 699 dir: disk0/10/14/35/13 datestamp: 2022-02-16 14:15:47 lastmod: 2022-02-16 14:15:47 status_changed: 2022-02-16 14:15:47 type: article metadata_visibility: show sword_depositor: 699 creators_name: Black, Stefanie AG creators_name: Stepanchuk, Anastasiia A creators_name: Templeton, George W creators_name: Hernandez, Yda creators_name: Ota, Tomoko creators_name: Roychoudhury, Shyamosree creators_name: Smith, Eric E creators_name: Barber, Philip A creators_name: Ismail, Zahinoor creators_name: Fischer, Karyn creators_name: Zwiers, Angela creators_name: Poulin, Marc J creators_name: Blennow, Kaj creators_name: Zetterberg, Henrik creators_name: Stys, Peter K creators_name: Tsutsui, Shigeki title: Diagnosing Alzheimer's Disease from Circulating Blood Leukocytes Using a Fluorescent Amyloid Probe ispublished: pub divisions: C07 divisions: F86 divisions: B02 divisions: UCL divisions: D07 keywords: Alzheimer’s disease, Aβ42, cerebrospinal fluid, conformationally-sensitive amyloid probes, p-Tau, peripheral blood mononuclear cells, spectral confocal microscopy, t-Tau note: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions. abstract: BACKGROUND: Toxic amyloid-β (Aβ) peptides aggregate into higher molecular weight assemblies and accumulate not only in the extracellular space, but also in the walls of blood vessels in the brain, increasing their permeability, and promoting immune cell migration and activation. Given the prominent role of the immune system, phagocytic blood cells may contact pathological brain materials. OBJECTIVE: To develop a novel method for early Alzheimer's disease (AD) detection, we used blood leukocytes, that could act as "sentinels" after trafficking through the brain microvasculature, to detect pathological amyloid by labelling with a conformationally-sensitive fluorescent amyloid probe and imaging with confocal spectral microscopy. METHODS: Formalin-fixed peripheral blood mononuclear cells (PBMCs) from cognitively healthy control (HC) subjects, mild cognitive impairment (MCI) and AD patients were stained with the fluorescent amyloid probe K114, and imaged. Results were validated against cerebrospinal fluid (CSF) biomarkers and clinical diagnosis. RESULTS: K114-labeled leukocytes exhibited distinctive fluorescent spectral signatures in MCI/AD subjects. Comparing subjects with single CSF biomarker-positive AD/MCI to negative controls, our technique yielded modest AUCs, which improved to the 0.90 range when only MCI subjects were included in order to measure performance in an early disease state. Combining CSF Aβ 42 and t-Tau metrics further improved the AUC to 0.93. CONCLUSION: Our method holds promise for sensitive detection of AD-related protein misfolding in circulating leukocytes, particularly in the early stages of disease. date: 2022-02-15 date_type: published publisher: IOS Press official_url: https://doi.org/10.3233/JAD-215402 oa_status: green full_text_type: other language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1913658 doi: 10.3233/JAD-215402 medium: Print-Electronic pii: JAD215402 lyricists_name: Zetterberg, Henrik lyricists_id: HZETT94 actors_name: Zetterberg, Henrik actors_name: Harriot, Anne-Marie actors_id: HZETT94 actors_id: AHARA72 actors_role: owner actors_role: impersonator full_text_status: public publication: Journal of Alzheimer's Disease volume: 85 number: 4 pagerange: 1721-1734 event_location: Netherlands citation: Black, Stefanie AG; Stepanchuk, Anastasiia A; Templeton, George W; Hernandez, Yda; Ota, Tomoko; Roychoudhury, Shyamosree; Smith, Eric E; ... Tsutsui, Shigeki; + view all <#> Black, Stefanie AG; Stepanchuk, Anastasiia A; Templeton, George W; Hernandez, Yda; Ota, Tomoko; Roychoudhury, Shyamosree; Smith, Eric E; Barber, Philip A; Ismail, Zahinoor; Fischer, Karyn; Zwiers, Angela; Poulin, Marc J; Blennow, Kaj; Zetterberg, Henrik; Stys, Peter K; Tsutsui, Shigeki; - view fewer <#> (2022) Diagnosing Alzheimer's Disease from Circulating Blood Leukocytes Using a Fluorescent Amyloid Probe. Journal of Alzheimer's Disease , 85 (4) pp. 1721-1734. 10.3233/JAD-215402 <https://doi.org/10.3233/JAD-215402>. Green open access document_url: https://discovery-pp.ucl.ac.uk/id/eprint/10143513/3/Zetterberg_Diagnosing%20Alzheimers%20Disease%20from%20Circulating%20Blood%20Leukocytes%20Using%20a%20Fluorescent%20Amyloid%20Probe.pdf