Evaluation of the methoxy-X04 derivative BSC4090 for diagnosis of prodromal and early Alzheimer’s disease from bioptic olfactory mucosa

Abstract

Alzheimer's disease (AD) pathology precedes the onset of clinical symptoms by several decades. Thus, biomarkers are required to identify prodromal disease stages to allow for the early and effective treatment. The methoxy-X04-derivative BSC4090 is a fluorescent ligand which was designed to target neurofibrillary tangles in AD. BSC4090 staining was previously detected in post-mortem brains and olfactory mucosa derived from AD patients. We tested BSC4090 as a potential diagnostic marker of prodromal and early AD using olfactory mucosa biopsies from 12 individuals with AD, 13 with mild cognitive impairment (MCI), and 10 cognitively normal (CN) controls. Receiver-operating curve analysis revealed areas under the curve of 0.78 for AD versus CN and of 0.86 for MCI due to AD versus MCI of other causes. BSC4090 labeling correlated significantly with cerebrospinal fluid levels of tau protein phosphorylated at T181. Using NMR spectroscopy, we find that BSC4090 binds to fibrillar and pre-fibrillar but not to monomeric tau. Thus, BSC4090 may be an interesting candidate to detect AD at the early disease stages.

Fluid Biomarkers in Alzheimer’s Disease and Other Neurodegenerative Disorders: Toward Integrative Diagnostic Frameworks and Tailored Treatments

“…Recently, BSC4090 (a fluorescent ligand targeting neurofibrillary tangles) proved to be an interesting candidate proxy of AD pathology modification in olfactory mucosa biopsies. It fairly distinguished AD from HC (AUROC 0.778) with good accuracy [96] (Table 2). RT-QuIC analyses for detection of α-syn in the olfactory mucosa of PD patients is reliable in both PD and prodromal PD patients [97], and in DLB and prodromal DLB patients too [98] (Table 2).…”

Making Sense of Patient-Derived iPSCs, Transdifferentiated Neurons, Olfactory Neuronal Cells, and Cerebral Organoids as Models for Psychiatric Disorders

“…For example, Alzheimer pathology, that is, Amyloid-ß aggregate and paired helical filament tau in neurites, is present in the olfactory epithelium, reflecting cortical lesions ( Arnold et al, 2010 ). Moreover, biopsied olfactory mucosa was recently used to develop a potential biomarker for prodromal stages of Alzheimer’s disease ( Pellkofer et al, 2019 ), underlining the great potential of this tissue type.…”

Diagnose It Yourself: Will There Be a Home Test Kit for Alzheimer’s disease?

“…There are contradictory reports, but there is evidence for a higher expression of amyloid-beta and paired helical filament tau in the olfactory epithelium of AD patients post mortem in contrast to controls and also to subjects with other neurodegenerative diseases [55]. The methoxy-X04 derivative BSC4090, a fluorescent ligand designed to target neurofibrillary tangles in AD in olfactory mucosa, might even allow for early differential diagnosis [56]. Thus, smears from the olfactory mucosa might be promising specimens to look into when developing easily applicable approaches for diagnostic implementations.…”