Pilot Study of Granulocyte-Colony Stimulating Factor for Treatment of Alzheimer's Disease

Article type: Research Article

Authors: Sanchez-Ramos, Juan^{a; b; c; *} | Cimino, Cynthia^{b; c} | Avila, Ross^c | Rowe, Amanda^d | Chen, Ren^e | Whelan, Glenn^f | Lin, Xiaoyang^a | Cao, Chuanhai^{a; d; f} | Ashok, Raj^a

Affiliations: [a] USF Health Byrd Alzheimer's Institute, Tampa, FL, USA | [b] Department of Neurology, University of South Florida, Tampa, FL, USA | [c] Department of Psychology, University of South Florida, Tampa, FL, USA | [d] Department of Molecular Pharmacology, University of South Florida, Tampa, FL, USA | [e] Office of Clinical Research, University of South Florida, Tampa, FL, USA | [f] College of Pharmacy, University of South Florida, Tampa, FL, USA

Correspondence: [*] Correspondence to: Juan Sanchez-Ramos, PhD, MD, Department of Neurology, College of Medicine, University of South Florida, 13220 Laurel Drive, Tampa, FL, USA. E-mail: [email protected].

Abstract: Human granulocyte colony-stimulating-factor (G-CSF) is widely used for treatment of neutropenia and to mobilize stem/progenitor cells for bone marrow transplantation. In studies of thousands of healthy donor subjects treated with G-CSF to mobilize stem/progenitor cells, the side-effect profile has been reported to be mild and reversible. In pre-clinical studies, G-CSF was reported to improve spatial learning performance and to markedly reduce amyloid deposition in hippocampus and entorhinal cortex in a murine model of Alzheimer's disease (AD). The present study investigated the effects of a five day schedule of G-CSF administration on tolerability, safety, and cognition in eight patients with mild to moderate stage AD. A double-blind placebo control, cross-over design was implemented. Treatment with G-CSF did not result in serious adverse events. The most common and expected side effects were transient increases in white blood cell count, myalgias and diffuse aching that improved with non-steroidal anti-inflammatory medications. Of a battery of cognitive tests administered using the CANTAB computerized system, only the mean paired associate learning (PAL total trials adjusted) was significantly improved at the final visit of the study compared to baseline values (p < 0.05). There were no significant differences in amyloid-β1-42 levels in cerebrospinal fluid measured two weeks after G-CSF and two weeks after placebo treatments. In conclusion, administration of G-CSF in a dosage regimen commonly used for bone marrow donors was well tolerated and safe, and provided a signal of positive change in a hippocampal-dependent task of cognitive performance.

Keywords: Alzheimer's disease, amyloid-β, computer assisted neuropsychological battery, cytokines, filgrastim, granulocyte-colony stimulating factor, NEUPOGEN^®, paired-associate learning

DOI: 10.3233/JAD-2012-120196

Journal: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 843-855, 2012