S-[¹⁸F]THK-5117-PET and [¹¹C]PIB-PET Imaging in Idiopathic Normal Pressure Hydrocephalus in Relation to Confirmed Amyloid-β Plaques and Tau in Brain Biopsies

Article type: Research Article

Authors: Leinonen, Ville^{a; b; *} | Rauramaa, Tuomas^c | Johansson, Jarkko^d | Bottelbergs, Astrid^e | Tesseur, Ina^e | van der Ark, Peter^e | Pemberton, Darrel^e | Koivisto, Anne M.^f | Jääskeläinen, Juha E.^a | Hiltunen, Mikko^{f; g} | Herukka, Sanna-Kaisa^f | Blennow, Kaj^{h; i} | Zetterberg, Henrik^{h; i; j; k} | Jokinen, Pekka^{d; l} | Rokka, Johanna^{m; n} | Helin, Semi^m | Haaparanta-Solin, Merja^{o; p} | Solin, Olof^{m; q; r} | Okamura, Nobuyuki^s | Kolb, Hartmuth C.^t | Rinne, Juha O.^{d; u}

Affiliations: [a] Institute of Clinical Medicine – Neurosurgery, University of Eastern Finland and Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland | [b] Unit of ClinicalNeuroscience, Neurosurgery, University of Oulu and Medical Research Center, Oulu University Hospital, Oulu, Finland | [c] Institute of Clinical Medicine – Pathology, University of Eastern Finland andDepartment of Pathology, Kuopio University Hospital, Kuopio, Finland | [d] Turku PET Centre, University of Turku, Turku, Finland | [e] Janssen Research and Development, A Division of Janssen Pharmaceutica, Beerse, Belgium | [f] Institute of Clinical Medicine – Neurology, Universityof Eastern Finland and Department of Neurology, Kuopio University Hospital, Kuopio, Finland | [g] Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland | [h] Clinical Neurochemistry Laboratory, Sahlgrenska Academy Hospital, Mölndal, Sweden | [i] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden | [j] Department of MolecularNeuroscience, Institute of Neurology, University College London, Queen, Square, UK | [k] UK DementiaResearch Institute, London, UK | [l] Department of Neurosurgery, Turku University Hospital, Turku, Finland | [m] Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Turku, Finland | [n] Athinoula A. Martinos Center, Department of Radiology, Massachusetts GeneralHospital, Harvard Medical School, Charlestown, MA, USA | [o] PET Preclinical Imaging Laboratory, Turku PET Centre, University of Turku, Turku, Finland | [p] MediCity Research Laboratory, University of Turku, Turku, Finland | [q] Department of Chemistry, University of Turku, Turku, Finland | [r] Accelerator Laboratory, Turku PET Centre, Åbo Akademi University, Turku, Finland | [s] Tohoku Medical and Pharmaceutical University, Sendai, Japan | [t] Janssen Research and Development, San Diego, CA, USA | [u] Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland

Correspondence: [*] Correspondence to: Ville Leinonen, MD, PhD, Department of Neurosurgery, Kuopio University Hospital, P.O. Box 100, FI-70029 KYS, Finland. Tel.: +358 40 514 7320/358 44 717 2303; Fax: +358 17 173 916; E-mail: ville.leinonen@kuh.fi.

Abstract: Background:Detection of pathological tau aggregates could facilitate clinical diagnosis of Alzheimer’s disease (AD) and monitor drug effects in clinical trials. S-[18F]THK-5117 could be a potential tracer to detect pathological tau deposits in brain. However, no previous study have correlated S-[18F]THK-5117 uptake in PET with brain biopsy verified tau pathology in vivo. Objective:Here we aim to evaluate the association between cerebrospinal fluid (CSF) AD biomarkers, S-[18F]THK-5117, and [11C]PIB PET against tau and amyloid lesions in brain biopsy. Methods:Fourteen patients with idiopathic normal pressure hydrocephalus (iNPH) with previous shunt surgery including right frontal cortical brain biopsy and CSF Aβ1 - 42, total tau, and P-tau181 measures, underwent brain MRI, [11C]PIB PET, and S-[18F]THK-5117 PET imaging. Results:Seven patients had amyloid-β (Aβ, 4G8) plaques, two both Aβ and phosphorylated tau (Pτ, AT8) and one only Pτ in biopsy. As expected, increased brain biopsy Aβ was well associated with higher [11C]PIB uptake in PET. However, S-[18F]THK-5117 uptake did not show any statistically significant correlation with either brain biopsy Pτ or CSF P-tau181 or total tau. Conclusions:S-[18F]THK-5117 lacked clear association with neuropathologically verified tau pathology in brain biopsy probably, at least partially, due to off-target binding. Further studies with larger samples of patients with different tau tracers are urgently needed. The detection of simultaneous Aβ and tau pathology in iNPH is important since that may indicate poorer and especially shorter response for CSF shunt surgery compared with no pathology.

Keywords: Alzheimer’s disease, amyloid-beta, idiopathic normal pressure hydrocephalus, neuropathology, PIB, positron emission tomography, PTHK-5117, tau, contstartabstract

DOI: 10.3233/JAD-180071

Journal: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 171-179, 2018