Brain metabolic effects of Neotrofin in patients with Alzheimer's disease

Neotrofin, a reported inducer of CNS neurotrophic factor synthesis and release, with memory-enhancing activity and demonstrated restoration of age-induced memory deficits in animals, was tested in patients with mild to moderate Alzheimer's disease. Nineteen subjects were treated with 1 week of low-dose (150 mg per day) and 1 week of high-dose (500 or 1000 mg per day) Neotrofin. Cognitive composite scores demonstrated improvement in memory (F=9.6, P=0.0004), executive functioning (P=0.004), and attention (P=0.004). PET scanning was obtained before, after low, and after high dosing. The brain areas most affected were the cerebellum, and sensory and prefrontal cortices, where increases in GMR (Glucose Metabolic Rate) were observed. Increases and decreases were observed in the posterior superior temporal (BA 22), parahippocampal, inferior temporal (BA 37, 20), and fusiform gyri as well as the superior parietal lobule and postcentral gyrus. There were strong hemispheric differences, producing opposite metabolic effects in homologous brain regions. Subcortically, the posterior thalamic region, meso-pontine tegmentum, and tectum had increases in GMR on the left side. At the low dose, GMR was generally increased, but to a lesser degree. The brain areas subserving memory, attention and executive functions were significantly altered in GMR by Neotrofin; however, the directions of these changes were complex. There were significant correlations between improvement in memory and executive function in brain areas involved in circuits subserving these functions. Thus, Neotrofin appears to induce metabolic changes in brain regions involved in circuits underlying memory, attention, and executive functioning.