Amyloid-β and Tau Dynamics in Human Brain Interstitial Fluid in Patients with Suspected Normal Pressure Hydrocephalus

Article type: Research Article

Authors: Herukka, Sanna-Kaisa^{a; b} | Rummukainen, Jaana^c | Ihalainen, Jouni^d | von und zu Fraunberg, Mikael^e | Koivisto, Anne M.^{a; b} | Nerg, Ossi^b | Puli, Lakshman K.^d | Seppälä, Toni T.^a | Zetterberg, Henrik^{f; g} | Pyykkö, Okko T.^e | Helisalmi, Seppo^a | Tanila, Heikki^d | Alafuzoff, Irina^h | Hiltunen, Mikko^{a; b; i} | Rinne, Jaakko^j | Soininen, Hilkka^{a; b} | Jääskeläinen, Juha E.^e | Leinonen, Ville^{e; *}

Affiliations: [a] Unit of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland | [b] Neurology of NeuroCenter, Kuopio University Hospital, Kuopio, Finland | [c] Department of Pathology, Kuopio University Hospital, Kuopio, Finland | [d] Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland | [e] Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland and Neurosurgery, Institute of Clinical Medicine, University of Eastern Finland Kuopio, Finland | [f] Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden | [g] UCL Institute of Neurology, Queen Square, London, United Kingdom | [h] Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University and Department of Pathology and Cytology, Uppsala University Hospital, Uppsala, Sweden | [i] Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland | [j] Department of Neurosurgery, Turku University Hospital and University of Turku, 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; ville.leinonen@kuh.fi

Abstract: Background: Amyloid-β (Aβ1 - 42), total tau (T-tau), and phosphorylated tau (P-tau181) in the cerebrospinal fluid (CSF) are the most promising biomarkers of Alzheimer’s disease (AD). Still, little is known about the dynamics of these molecules in the living brain. In a transgenic mouse brain, soluble Aβ decreases with increasing age and advanced Aβ pathology as seen similarly in CSF. Objective: To assess the relationship between AD-related pathological changes in human brain tissue, ventricular and lumbar CSF, and brain interstitial fluid (ISF). Methods: Altogether 11 patients with suspected idiopathic normal pressure hydrocephalus underwent frontal cortical brain biopsy, 24-h intraventricular pressure monitoring, and a microdialysis procedure. AD-related biomarkers were analyzed from brain tissue, CSF, and ISF. Results: ISF T-tau levels decreased strongly within the first 12 h, then plateauing until the end of the experiment. Aβ1 - 42 and P-tau181 remained stable during the experiment (n = 3). T-tau and P-tau were higher in the ISF than in ventricular or lumbar CSF, while Aβ1 - 42 levels were within similar range in both CSF and ISF samples. ISF P-tau correlated with the ventricular CSF T-tau (r = 0.70, p = 0.017) and P-tau181 (r = 0.64, p = 0.034). Five patients with amyloid pathology in the brain biopsy tended to reveal lower ISF Aβ1 - 42 levels than those six without amyloid pathology. Conclusions: This is the first study to report ISF Aβ and tau levels in the human brain without significant brain injury. The set-up used enables sampling from the brain ISF for at least 24 h without causing adverse effects due to the microdialysis procedure to follow the dynamics of the key molecules in AD pathogenesis in the living brain at various stages of the disease.

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, normal pressure hydrocephalus, tau

DOI: 10.3233/JAD-142862

Journal: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 261-269, 2015