Year: 2023
Type: article
Study design: Observational Study
Abstract: Background Recent studies suggest that microtubule‐binding region (MTBR) tau fragments may be markers of tau tangles in Alzheimer’s disease (AD) when used in ratio with total tau (MTBR‐tau/T‐tau) to normalize for T‐tau secretion. One such candidate marker is MTBR‐tau containing residue 368 (MTBR‐tau368). In this study, it was cross‐sectionally evaluated in participants from a memory clinic cohort and an autopsy series. Methods We included Aβ‐negative cognitively unimpaired (CU) individuals, individuals in the AD continuum (Aβ‐positive CU, mild cognitive impairment (MCI) and AD dementia), and with non‐AD dementia from the BioFINDER‐1 study, who all underwent [18F]‐flortaucipir‐PET. Further, we included CU and CI participants from UCSD Alzheimer’s disease research center (UCSD‐ADRC) who underwent lumbar puncture (LP) antemortem and then donated their brain for autopsy, examining AD neuropathologic change (ADNC) and non‐AD pathologies. All participants had immunoassay‐based CSF measures of T‐tau and MTBR‐tau368 by commercial immunoassays (Euroimmun [BioFINDER‐1] and Lumipulse [UCSD‐ADRC] T‐tau) and an in‐house Single molecule array (Simoa) assay, respectively. Statistical analyses were performed using linear models (covarying for age and sex) and Pearson correlations. Results Sixty‐seven individuals from UCSD‐ADRC (mean [SD] age at LP 74.3 [8.4] years, 4.3 [2.1] years before death) and 181 from BioFINDER‐1 (72.5 [7.4] years) were included for this study. There were no group‐level differences in MTBR‐tau368 levels alone in any of the cohorts. In the UCSD‐ADRC cohort, MTBR‐tau368/T‐tau was decreased in participants with high (estimated marginal mean [EM = 0.06) vs. low (EM = 0.09, P = 0.01) or no (EM = 0.1, P = 0.001) ADNC and with higher Braak stage (V‐VI; EM = 0.06 vs. III‐IV; EM = 0.08, P<0.05, and I‐II; EM = 0.09, P<0.001). In BioFINDER‐1, Aβ‐positive MCI and AD dementia had lower MTBR‐tau368/T‐tau (EM∼0.04) compared with all other groups (EM = 0.06‐0.07, P<0.05‐<0.001). Further, MTBR‐tau368/T‐tau inversely correlated with tau‐PET in Braak‐like regions III‐IV and V‐VI (r = ‐0.35 and ‐0.42, P<0.001). MTBR‐tau368/T‐tau was unchanged in individuals in the frontotemporal dementia (FTD) spectrum (behavioral variant FTD/semantic dementia, and corticobasal syndrome/progressive supranuclear palsy). Conclusion Concordant with recent data, MTBR‐tau fragments alone do not change in AD or other neurodegenerative disorders. However, when normalizing MTBR fragments to T‐tau secretion, their capability of reflecting the extent of tau pathology provides opportunities of staging AD using CSF biomarkers.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.079611
Authors: Joel Simrén, Shorena Janelidze, Przemyslaw Radoslaw Kac, Thomas K Karikari, Denis Smirnov, Hlin Kvartsberg, Fernando Gonzalez‐Ortiz, Emma Sjons, Niklas Mattsson‐Carlgren, Wagner Scheeren Brum, Sebastian Palmqvist, Nicholas J. Ashton, Henrik Zetterberg, Douglas R. Galasko, Oskar Hansson, Kaj Blennow
Institutions: Sahlgrenska University Hospital, University of Gothenburg, Lund University, University of Pittsburgh, University of California San Diego, Skåne University Hospital, Universidade Federal do Rio Grande do Sul, King's College London, Stavanger University Hospital, University of Wisconsin–Madison, UK Dementia Research Institute, UCL Queen Square Institute of Neurology, University College London, VA San Diego Healthcare System
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4390195057