Physiologic modulation of natural killer cell activity as an index of Alzheimer's disease progression

Abstract

Patients with Alzheimer's disease (AD) are characterized by an altered sensitivity to cortisol-mediated modulation of circulating lymphocytes. Longitudinal studies are needed to address the clinical applicability of these abnormalities as prognostic factors. Therefore, we designed a longitudinal study to address the clinical applicability of physiologic modulation of Natural Killer (NK) cell activity as a prognostic factor in AD. NK activity was assessed as baseline measurement and in response to modulation by cortisol at 10(-6)M. To verify the immunophysiological integrity of the NK cell population, we tested augmentation of NK cytotoxicity by human recombinant interleukin (IL)-2 (100 IU/ml) as control. The response to modulation by cortisol or by IL-2 was significantly greater in patients with AD. Based on change in the Mini-Mental State score at entry and at 18 months, patients with AD could be assigned to a "fast progression" (Delta > 2 points) or to a "slow progression" group (Delta <or= 2 points). The change in the response of NK cytotoxic activity to cortisol, and the strength of the association of this parameter with circulating activated T cells in time was greater in patients with Fast Progression vs. Slow Progression AD. These results suggest that changes in the response of NK cells to negative (e.g., cortisol) or positive modifiers (e.g., IL-2) follow progression of AD.

Figure 1

(a) Pattern of progression of AD symptoms in terms of the score for the Mini-Mental State Examination-corrected for educational level and ethnicity at 0 to 18 months. The data in the figure (mean + SD) show that the score on the MMSE-C dropped significantly faster in patients with Fast Progression AD (p<0.05), compared to their cohorts with Slow Progression AD. (closed squares: control subjects; open squares: patients with Slow Progression AD; closed circles: patients with Fast Progression AD); (b) Pattern of progression of AD symptoms in terms of the score for the Activities of Daily Living (ADL) (data presented as median values). (closed squares: control subjects; open squares: patients with Slow Progression AD; closed circles: patients with Fast Progression AD); (c) Pattern of change of the modulatory response of NK activity in time to cortisol among normal controls and patients with Slow Progression and Fast Progression AD at six month intervals between entry and 18 month; (d) Pattern of change in NK modulation by IL- 2 among normal controls and patients with Slow Progression and Fast Progression AD at six month intervals between entry and 18 month. (data are presented as median group percent change from baseline untreated cells to cells treated with the physiological modulator). (closed squares: control subjects; open squares: patients with Slow Progression AD; closed circles: patients with Fast Progression AD)