Age-related increases in basal ganglia glutamate are associated with TNF, reduced motivation and decreased psychomotor speed during IFN-alpha treatment: Preliminary findings

Abstract

Inflammation-induced alterations in central nervous system (CNS) metabolism have focused on glutamate. At excessive concentrations, glutamate is toxic to glia and neurons, and inflammatory cytokines have been shown to influence glutamate turnover by blocking glutamate reuptake and increasing glutamate release. Increased glutamate has also been found in depression, a disorder associated with increased inflammation. Data by our group have shown increased glutamate as measured by magnetic resonance spectroscopy (MRS) in basal ganglia and dorsal anterior cingulate cortex of patients administered the inflammatory cytokine interferon (IFN)-alpha. Given data that increasing age is associated with an exaggerated CNS inflammatory response, we examined whether older age (>55years) would be associated with a greater IFN-alpha-induced increase in CNS glutamate. Using a longitudinal design, 31 patients with hepatitis C virus (HCV) underwent MRS, blood sampling for inflammatory markers, and behavioral assessments before (Visit 1) and after 4weeks (Visit 2) of either IFN-alpha (n=17) or no treatment (n=14). Older patients treated with IFN-alpha exhibited a significantly greater increase in glutamate from Visit 1 to Visit 2 as reflected by the glutamate/creatine ratio (Glu/Cr) in left basal ganglia compared to older controls and younger IFN-alpha-treated and untreated subjects. In addition, increased Glu/Cr in older but not younger IFN-alpha-treated and untreated patients was associated with increased tumor necrosis factor, reduced motivation as measured by the Multidimensional Fatigue Inventory and increased choice movement time on the Cambridge Neuropsychological Test Automated Battery. Taken together, these preliminary data support the notion that older age may interact with inflammation to exaggerate the effects of inflammatory stimuli on CNS glutamate and behavior.

Keywords: Aging; Basal ganglia; Cytokine; Glutamate; IFN-alpha; Inflammation; Motivation; Psychomotor speed; TNF.

Figure 1. Increased Left Basal Ganglia Glutamate in Older IFN-alpha-Treated Subjects and Correlation of Left Basal Ganglia Glutamate with TNF, Reduced Motivation and Motor Slowing in Older Hepatitis C Subjects

A. Delta (Visit2-Visit1) log left basal ganglia glutamate (Glu/Cr) is higher in older (>55 years) interferon (IFN)-treated subjects than older controls and younger (<55 years) IFN-alpha-treated and untreated subjects. B. Increased delta log TNF correlates with increased delta log left basal ganglia Glu/Cr in older IFN-alpha-treated and control subjects (B=0.61, p=0.026). C. Increased delta log left basal Glu/Cr correlates with increased delta reduced motivation in older IFN-alpha-treated and untreated subjects (B=0.67, p=0.014). D. Increased delta log left basal ganglia Glu/Cr correlates with increased delta choice movement time in older IFN-alpha-treated and untreated subjects (B=0.61, p=0.04). Of note, one subject did not complete the CANTAB reaction time task. *-p<0.05, ***-p<0.001; Open circles: IFN-alpha; Closed circles: controls