Preclinical Cerebrospinal Fluid and Volumetric Magnetic Resonance Imaging Biomarkers in Swedish Familial Alzheimer's Disease

Article type: Research Article

Authors: Thordardottir, Steinunn^{a; b; *} | Ståhlbom, Anne Kinhult^{a; c} | Ferreira, Daniel^c | Almkvist, Ove^d | Westman, Eric^c | Zetterberg, Henrik^{e; f} | Eriksdotter, Maria^{b; c} | Blennow, Kaj^e | Graff, Caroline^{a; b}

Affiliations: [a] Karolinska Institutet, Department NVS, Division of Neurogeriatrics, Center for Alzheimer Disease Research, Huddinge, Sweden | [b] Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden | [c] Karolinska Institutet, Department of NVS, Division for Clinical Geriatrics, Center for Alzheimer Disease Research, Huddinge, Sweden | [d] Karolinska Institutet, Department of NVS, Center for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Huddinge, Sweden | [e] Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden | [f] UCL Institute of Neurology, Queen Square, London, UK

Correspondence: [*] Correspondence to: Steinunn Thordardottir, Karolinska Institutet, Department of NVS, Center for Alzheimer Research, Division for Neurogeriatrics, 141 57 Huddinge, Sweden. Tel.: +46 702 702 066; Fax: +46 85 858 3610; E-mail: [email protected].

Abstract: Background:It is currently believed that therapeutic interventions will be most effective when introduced at the preclinical stage of Alzheimer's disease (AD). This underlines the importance of biomarkers to detect AD pathology in vivo before clinical disease onset. Objective:To examine the evolution of cerebrospinal fluid (CSF) biomarker and brain structure changes in the preclinical phase of familial AD. Methods:The study included members from four Swedish families at risk for carrying an APPswe, APParc, PSEN1 H163Y, or PSEN1 I143T mutation. Magnetic resonance imaging (MRI) scans were obtained from 13 mutation carriers (MC) and 20 non-carriers (NC) and analyzed using vertex-based analyses of cortical thickness and volume. CSF was collected from 10 MC and 12 NC from familial AD families and analyzed for Aβ42, total tau (T-tau) and phospho-tau (P-tau). Results:The MC had significantly lower levels of CSF Aβ42 and higher levels T-tau and P-tau than the NC. There was a trend for a decrease in Aβ42 15–20 years before expected onset of clinical symptoms, while increasing T-tau and P-tau was not found until close to the expected clinical onset. The MC had decreased volume on MRI in the left precuneus, superior temporal gyrus, and fusiform gyrus. Conclusions:Aberrant biomarker levels in CSF as well as regional brain atrophy are present in preclinical familial AD, several years before the expected onset of clinical symptoms.

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, genetics, magnetic resonance imaging, natural history studies, preclinical

DOI: 10.3233/JAD-140339

Journal: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1393-1402, 2015