THE ROLE OF TUMOR NECROSIS FACTOR‐ALPHA IN COGNITIVE IMPROVEMENT AFTER PEROXISOME PROLIFERATOR‐ACTIVATOR RECEPTOR GAMMA AGONIST PIOGLITAZONE TREATMENT IN ALZHEIMER'S DISEASE (2010)

To the Editor: Some clinical trials have shown that agonists of the nuclear receptor peroxisome proliferator-activator receptor gamma (PPRAγ) improve cognition and memory in patients with Alzheimer's disease (AD).1,2 A pilot study demonstrated that 6 months of treatment with a PPARγ agonist, pioglitazone, improved cognition and hyperinsulinemia in patients with mild AD with type II diabetes mellitus,3 although the reason for these benefits is not fully understood. In animal models of AD, pioglitazone treatment resulted in the reduction of numbers of activated microglia associated with a lower plaque burden, partly by suppressing proinflammatory gene expression.4 The aim of the present study was to investigate the role of inflammatory-associated proteins in the improvement of cognition after pioglitazone treatment in patients with mild AD. A 6-month, randomized, open-controlled trial was conducted in patients with mild AD associated with type II diabetes mellitus. Thirty-four patients with probable AD5 were randomly assigned to treatment with pioglitazone 15 mg daily (n=17, pioglitazone group) or not (n=17, control group). Twenty-six of these patients were included in a 2009 study3 of patients with mild AD. The study protocol has been described elsewhere in detail.3 In this study, plasma cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hs-CRP), were quantified at baseline and Month 6 using commercially available enzyme-linked immunoassays and nephrometry, respectively. The minimum detectable concentrations were 0.5 pg/mL, 0.2 pg/mL, and 0.02 mg/dL, respectively. Values were expressed as means ± standard deviations. Statistical analysis was performed using the Student t-test, chi-square test, Mann-Whitney U test, Wilcoxon signed-rank test, and Spearman rank correlation test. Table 1 shows comparisons of subject characteristics and Alzheimer's Disease Assessment Scale Cognitive Subscale, Japanese version (ADAS-Jcog) scores, plasma cytokines, and hs-CRP changes. There were no significant differences between the pioglitazone group and the control group in terms of age, sex, education, duration of symptoms, Mini-Mental State Examination (MMSE) score, apolipoprotein E ɛ4 status, or prevalence of use of donepezil. At baseline, no significant differences were found in ADAS-Jcog scores, plasma cytokines, or hs-CRP levels between the groups. At Month 6, ADAS-Jcog scores had decreased significantly in the pioglitazone group and increased significantly in the control group. There was a significant difference between the groups in ADAS-Jcog score changes (Month 6–baseline). When compared with baseline values, TNF-α, IL-6, and hs-CRP levels at Month 6 decreased in the pioglitazone group, whereas they increased in the control group, but no statistically significant change in either value was found in the two groups. There was a significant difference in TNF-α level changes (Month 6–baseline) between the groups. Changes in ADAS-Jcog scores significantly correlated with changes in TNF-α (correlation coefficient (r)=0.38, P=.04) but not in IL-6 (r=0.19) and hs-CRP levels (r=0.14). During the study, both groups showed stable fasting plasma glucose and hemoglobin A1c levels. When compared with baseline, fasting immunoreactive insulin levels at Month 6 decreased significantly in the pioglitazone group (from 7.8 ± 3.9 to 5.7 ± 2.4 μU/mL, P<.05) but not in the control group (from 6.7 ± 4.8 to 6.5 ± 2.9 μU/mL). It was found that reduction of TNF-α levels after pioglitazone treatment was associated with cognitive improvement. A previous study found that PPARγ agonists inhibit Aβ production stimulated by inflammatory cytokines.6 Proinflammatory cytokine TNF-α, which plays a role in immune system to brain communication, contributes to an exacerbation of neurodegeneration by microglial activation. A recent study showed that high serum TNF-α is associated with long-term cognitive decline in community-dwelling subjects with AD.7 An increase in TNF-α regulates synaptic scaling and results in disease progression in AD.8 Therefore, treatment to reduce TNF-α levels might provide some therapeutic benefits for AD. Although a number of studies have examined potential mechanisms through which PPARγ might act to ameliorate AD pathogenesis and progression, the anti-inflammatory action of PPARγ agonists is at least one plausible explanation for the beneficial effect on AD. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Haruo Hanyu: study concept and design, acquisition of subjects and data, analysis and interpretation of data, and preparation of letter. Tomohiko Sato, Hirofumi Sakurai, and Toshihiko Iwamoto: acquisition of subjects and data analysis. Sponsor's Role: None.