Ultrasensitive and selective detection of 3-repeat tau seeding activity in Pick disease brain and cerebrospinal fluid

Eri Saijo, Bernardino Ghetti, Gianluigi Zanusso, Adrian Oblak, Jennifer L. Furman, Marc I. Diamond, Allison Kraus, Byron Caughey

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The diagnosis and treatment of diseases involving tau-based pathology such as Alzheimer disease and certain frontotemporal dementias is hampered by the inability to detect pathological forms of tau with sufficient sensitivity, specificity and practicality. In these neurodegenerative diseases, tau accumulates in self-seeding filaments. For example, Pick disease (PiD) is associated with frontotemporal degeneration and accumulation of 3-repeat (3R) tau isoforms in filaments constituting Pick bodies. Exploiting the self-seeding activity of tau deposits, and using a 3R tau fragment as a substrate, we have developed an assay (tau RT-QuIC) that can detect tau seeds in 2 µl aliquots of PiD brain dilutions down to 10−7–10−9. PiD seeding activities were 100-fold higher in frontal and temporal lobes compared to cerebellar cortex. Strikingly, this test was 103- to 105-fold less responsive when seeded with brain containing predominant 4-repeat (4R) tau aggregates from cases of corticobasal degeneration, argyrophilic grain disease, and progressive supranuclear palsy. Alzheimer disease brain, with 3R + 4R tau deposits, also gave much weaker responses than PiD brain. When applied to cerebrospinal fluid samples (5 µl), tau RT-QuIC analyses discriminated PiD from non-PiD cases. These findings demonstrate that abnormal tau aggregates can be detected with high sensitivity and disease-specificity in crude tissue and fluid samples. Accordingly, this tau RT-QuIC assay exemplifies a new approach to diagnosing tauopathies and monitoring therapeutic trials using aggregated tau itself as a biomarker.

Original languageEnglish (US)
Pages (from-to)1-15
Number of pages15
JournalActa Neuropathologica
DOIs
StateAccepted/In press - Mar 14 2017

Fingerprint

Pick Disease of the Brain
Cerebrospinal Fluid
Alzheimer Disease
Tauopathies
Progressive Supranuclear Palsy
Sensitivity and Specificity
Frontotemporal Dementia
Cerebellar Cortex
Brain
Frontal Lobe
Temporal Lobe
Neurodegenerative Diseases
Seeds
Protein Isoforms
Biomarkers
Pathology

Keywords

  • Alzheimer's
  • Biomarker
  • Diagnosis
  • Pick’s disease
  • RT-QuIC
  • Tau aggregate
  • Tauopathy

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Ultrasensitive and selective detection of 3-repeat tau seeding activity in Pick disease brain and cerebrospinal fluid. / Saijo, Eri; Ghetti, Bernardino; Zanusso, Gianluigi; Oblak, Adrian; Furman, Jennifer L.; Diamond, Marc I.; Kraus, Allison; Caughey, Byron.

In: Acta Neuropathologica, 14.03.2017, p. 1-15.

Research output: Contribution to journalArticle

Saijo, Eri ; Ghetti, Bernardino ; Zanusso, Gianluigi ; Oblak, Adrian ; Furman, Jennifer L. ; Diamond, Marc I. ; Kraus, Allison ; Caughey, Byron. / Ultrasensitive and selective detection of 3-repeat tau seeding activity in Pick disease brain and cerebrospinal fluid. In: Acta Neuropathologica. 2017 ; pp. 1-15.
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