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[18F]Flutemetamol PET imaging and cortical biopsy histopathology for fibrillar amyloid β detection in living subjects with normal pressure hydrocephalus: pooled analysis of four studies

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Abstract

Molecular imaging techniques developed to ‘visualize’ amyloid in vivo represent a major achievement in Alzheimer’s disease (AD) research. This pooled analysis of four studies determined the level of association between uptake of the fibrillar amyloid β positron emission tomography (PET) imaging agent [18F]flutemetamol (Pittsburgh Compound B analog with a 5.5 times longer half-life to enable it to be used in the clinical setting) and neuritic plaques and fibrillar amyloid β measured by pathologic staining of cortical region biopsy samples. Fifty-two patients with suspected normal pressure hydrocephalus underwent prospective (n = 30) or retrospective (n = 22) [18F]flutemetamol PET imaging for detection of cerebral cortical fibrillar amyloid β and cortical brain biopsy during intracranial pressure measurement or ventriculo-peritoneal shunting. [18F]Flutemetamol uptake was quantified using standardized uptake value ratio (SUVR) with cerebellar cortex as the reference region. Tissue fibrillar amyloid β was evaluated using immunohistochemical monoclonal antibody 4G8 and histochemical agents Thioflavin S and Bielschowsky silver stain, and an overall pathology result based on all available immunohistochemical and histochemical results. Biopsy site and contralateral [18F]flutemetamol SUVRs were significantly associated with neuritic plaque burden assessed with Bielschowsky silver stain (r spearman’s = 0.61, p = 0.0001 for both), as was the composite SUVR with biopsy pathology (r spearman’s = 0.74, p < 0.0001). SUVR and immunohistochemical results with 4G8 for detecting fibrillar amyloid β were similar. Blinded image evaluation showed strong agreement between readers (κ = 0.86). Overall sensitivity and specificity by majority read were 93 and 100 %. Noninvasive in vivo [18F]flutemetamol PET imaging demonstrates strong concordance with histopathology for brain fibrillar amyloid β, supporting its promise as a tool to assist physicians with earlier detection of the disease process and making diagnostic decisions about concomitant AD and other diseases associated with brain amyloidosis.

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Acknowledgments

We thank all the patients and their relatives for participation in the study. The referring physicians and the staff of University of Pennsylvania, Johns Hopkins Medical Institution, and Turku PET Centers are gratefully acknowledged for excellent collaboration. We acknowledge the staff of the i3 Statprobe, USA, for biometric services, programming, and statistical analyses, and SJ Berman Services, LLC for editorial assistance (both organizations were funded by GE Healthcare). We are grateful to Kerstin Heurling (GE Healthcare) for technical support with VOI placement for the imaging data analysis and illustrations. The authors wish to thank all involved GE Healthcare study team members for operational support, and data, programming, and statistical management. The study was entirely funded by GE Healthcare.

Conflict of interest

Chris Buckley, Adrian Smith, Paul Sherwin, Gill Farrar, Marita Kailajärvi and Igor D Grachev are employees of GE Healthcare. Richard McLain is a contract-consultant of GE Healthcare. There are no other potential competing interests.

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Authors and Affiliations

  1. Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland

    Juha O. Rinne

  2. Johns Hopkins Medical Institution, Baltimore, MD, USA

    Dean F. Wong

  3. Department of Neurology, Penn Memory Center, University of Pennsylvania, Philadelphia, PA, USA

    David A. Wolk

  4. Department of Neurosurgery, KUH NeuroCenter, Kuopio University Hospital, Kuopio, Finland

    Ville Leinonen

  5. Department of Psychiatry, Penn Memory Center, University of Pennsylvania, Philadelphia, PA, USA

    Steven E. Arnold

  6. Medical Diagnostics, GE Healthcare, Amersham, HP7 9LL, UK

    Chris Buckley, Adrian Smith & Gill Farrar

  7. PFP Statistical Consulting, LLC, Livonia, MI, USA

    Richard McLain

  8. Medical Diagnostics, GE Healthcare, Princeton, NJ, USA

    Paul F. Sherwin & Igor D. Grachev

  9. Medical Diagnostics, GE Healthcare, Turku, Finland

    Marita Kailajärvi

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  1. Juha O. Rinne
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Correspondence to Igor D. Grachev.

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Rinne, J.O., Wong, D.F., Wolk, D.A. et al. [18F]Flutemetamol PET imaging and cortical biopsy histopathology for fibrillar amyloid β detection in living subjects with normal pressure hydrocephalus: pooled analysis of four studies. Acta Neuropathol 124, 833–845 (2012). https://doi.org/10.1007/s00401-012-1051-z

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