Correlations between Alzheimer’s Disease Cerebrospinal Fluid Biomarkers and Cerebral Glucose Metabolism after 12 Months of Phenserine Treatment

Article type: Research Article

Authors: Nordberg, Agneta^{a; b; *} | Kadir, Ahmadul^{a; b} | Andreasen, Niels^b | Almkvist, Ove^{a; c} | Wall, Anders^d | Långström, Bengt^f | Zetterberg, Henrik^g

Affiliations: [a] Karolinska Institutet, Dept NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Huddinge, Sweden | [b] Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden | [c] Department of Psychology, Stockholm University, Stockholm, Sweden | [d] Section of Nuclear Medicine & PET, Department of Radiology, Oncology and Radiation Sciences, Uppsala University, Uppsala, Sweden | [e] Institute of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry, Göteborg University, Göteborg, Sweden | [f] Department of Biochemistry and Organic Chemistry, Uppsala University, Uppsala, Sweden | [g] Institute of Neuroscience and Physiology, Clinical Neurochemistry Laboratory, Göteborg University, Göteborg, Sweden

Correspondence: [*] Correspondence to: Agneta Nordberg, MD PhD, Karolinska Institutet, Dept NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Novum Floor-5, S-141 87 Huddinge,Sweden. Tel.: +46 8 585 854 67; Fax: +46 8 585 854 70; [email protected]

Abstract: New therapeutic strategies in Alzheimer’s disease (AD) are focused on targeting amyloid-β (Aβ) to modify the underlying cause of the disease rather than just the symptoms. The aim of this study was to investigate the long-term effects of treatment with the anti-Aβ compound phenserine on (i) cerebrospinal fluid (CSF) biomarkers for Aβ and tau pathology and (ii) brain metabolism as assessed by the regional cerebral metabolic rate for glucose (rCMRglc), using positron emission tomography. Twenty patients with mild AD were included in the study and after 12 months treatment with phenserine, CSF Aβ 40 and α- and β-secretase-cleaved soluble amyloid-β protein precursor (sAβPP) levels had significantly increased and rCMRglc had stabilized. Levels of CSF Aβ 40 and sAβPP correlated positively with rCMRglc and cognition while CSF Aβ 42 levels, the Aβ 42/40 ratio, P-tau, and T-tau correlated negatively with rCMRglc and cognition. In summary, long-term phenserine treatment resulted in increased levels of CSF Aβ 40, sAβPPα, and sAβPPβ, which positively correlated with improvements in rCMRglc and cognition. The study illustrates the value of using biomarkers in the CSF and brain for evaluation of drug effects.

Keywords: Alzheimer’s disease, cerebral glucose metabolism, cerebrospinal fluid, phenserine, positron emission tomography

DOI: 10.3233/JAD-132474

Journal: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 691-704, 2015