Intracerebroventricular Infusion of Nerve Growth Factor in Three Patients with Alzheimer’s Disease

Abstract

Nerve growth factor (NGF) is important for the survival and maintenance of central cholinergic neurons, a signalling system impaired in Alzheimer’s disease. We have treated 3 patients with Alzheimer’s disease with a total of 6.6 mg NGF administered continuously into the lateral cerebral ventricle for 3 months in the first 2 patients and a total of 0.55 mg for 3 shorter periods in the third patient. The patients were extensively evaluated with clinical, neuropsychological, neurophysiological and neuroradiological techniques. Three months after the NGF treatment ended, a significant increase in nicotine binding was found in several brain areas in the first 2 patients and in the hippocampus in the third patient as studied by positron emission tomography. A clear cognitive amelioration could not be demonstrated, although a few neuropsychology tests showed slight improvements. The amount of slow-wave cortical activity as studied by electroencephalography was reduced in the first 2 patients. Two negative side effects occurred with NGF treatment: first, a dull, constant back pain was observed in all 3 patients, which in 1 patient was aggravated by axial loading resulting in sharp, shooting pain of short duration. When stopping the NGF infusion, the pain disappeared within a couple of days. Reducing the dose of NGF lessened the pain. Secondly, a marked weight reduction during the infusion with a clear weight gain after ending the infusion was seen in the first 2 patients. We conclude from this limited trial that, while long-term intracerebroventricular NGF administration may cause certain potentially beneficial effects, the intraventricular route of administration is also associated with negative side effects that appear to outweigh the positive effects of the present protocol. Alternative routes of administration, and/or lower doses of NGF, perhaps combined with low doses of other neurotrophic factors, may shift this balance in favor of positive effects.

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

“…Intracerebroventricular infusion of NGF to treat Alzheimer's disease was halted in a trial of 3 individuals due to the induction of pain and weight loss during the course of treatment [139]. In this case, the induction of neuropathic pain and the effects on the hypothalamus were consistent with the preclinical literature on intracerebroventricular infusion of NGF [140].…”

Selectivity of Cell Signaling in the Neuronal Response Based on NGF Mutations and Peptidomimetics in the Treatment of Alzheimers Disease

“…However, these forms of therapy provide the greatest benefit during early stages of AD before cholinergic deficits set in. Initial positive results in rat and primate animal models supported studies of NGF in clinical trials of AD (Bishop et al, 2008;Eriksdotter Jonhagen et al, 1998;Tuszynski et al, 2005). The early clinical trials met with a lack of success due to lack of efficacy, toxicity or both.…”

Neuroprotective strategies in Alzheimer’s disease

“…71 In the limited clinical experience assessing NGF actions in AD patients, NGF was administered to three patients via intraventricular infusion over a period of up to three months. 72 No significant improvement in cognition was detected and patients experienced back pain and weight loss. In an ongoing phase I trial, NGF is being delivered to the basal forebrain via intraparenchymal grafting of autologous fibroblasts engineered to secrete NGF.…”