PIOGLITAZONE IMPROVED COGNITION IN A PILOT STUDY ON PATIENTS WITH ALZHEIMER'S DISEASE AND MILD COGNITIVE IMPAIRMENT WITH DIABETES MELLITUS (2008)

To the Editor: Accumulating evidence suggests that the insulin resistance and peripheral hyperinsulinemia associated with type II diabetes mellitus (DM) promote Alzheimer's disease (AD) pathogenesis.1 Pharmacological treatment with thiazolidinedions such as rosiglitazone and pioglitazone, agonists of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), may offer some therapeutic relief of AD by lowering peripheral insulin and enhancing insulin sensitivity. In addition, PPARγ agonists have been shown to reduce beta-amyloid accumulation and inflammatory reactants and exhibit neuroprotective effects.2 It was recently demonstrated that 6 months of treatment with rosiglitazone preserved cognitive function in patients with AD and amnestic mild cognitive impairment (MCI),3,4 although there has been no report examining the effects of pioglitazone on cognitive function in patients with AD. The present study was designed to determine whether pioglitazone would have beneficial effects in patients with AD and MCI with type II DM. This was a prospective randomized, open-controlled study. Thirty-two patients with mild to moderate AD (Mini-Mental State Examination (MMSE) score of 16–26) and amnestic MCI who were treated with oral hypoglycemic medications or diet for type II DM were enrolled after providing informed consent. Each diagnosis was made using the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria5 for probable AD (26 patients) and Petersen's criteria6 for amnestic MCI (6 patients). Subjects using insulin were excluded. Patients were randomly assigned to treatment with pioglitazone 15 to 30 mg daily (n=15, pioglitazone group) or not (n=17, control group) in addition to their previous treatment for control of DM. Patients taking donepezil (a cholinesterase inhibitor) were enrolled, provided that the dose had remained unchanged from 6 months before participation through study completion. No subjects were taking any medication known to affect cognition or behavior during the study. Changes from baseline to Month 6 in the MMSE, Alzheimer's Disease Assessment Scale—Cognitive Subscale Japanese version (ADAS-Jcog), and Wechsler Memory Scale—Revised (WMS-R) logical memory-I were assessed. Additional measures included fasting plasma glucose (FPG), hemoglobin A1c, fasting immunoreactive insulin (FIRI), and the homeostasis model assessment ratio (HOMA-R). Values were expressed as means±standard deviations. Statistical analysis was performed using the Student t-test, the chi-square test, the Mann-Whitney U-test, and the Wilcoxon signed-rank test. At baseline, there were no significant differences between the pioglitazone group and the control group in age (76.5±5.8 vs 77.9±6.2), sex (7 men/8 women vs 9 men/8 women), diagnosis (12 AD/3 MCI vs 14 AD/3 MCI), education (12.3±2.7 vs 12.0±2.6 years), duration of symptoms (2.9±0.8 vs 3.0±0.9 years), or use of donepezil (6 patients vs 7 patients). Table 1 shows metabolic and cognitive changes between baseline and Month 6. At baseline, FPG, hemoglobin A1c, FIRI, and HOMA-R were comparable in the two groups. The pioglitazone group showed a significant decrease in FIRI and HOMA-R at Month 6 from baseline, but the control group showed no significant changes. At baseline, no significant differences were found on measures of cognition between the two groups. At Month 6, the ADAS-Jcog scores decreased significantly in the pioglitazone group, where they increased significantly in the control group. The WMS-R logical memory-I scores significantly increased in the pioglitazone group, but not in the control group. Neither groups showed any significant change on MMSE score at Month 6. Although only three patients in the pioglitazone group had mild peripheral edema, the adverse effect was tolerated without discontinuing the study medication. In animal models of AD, the PPARγ agonist pioglitazone has been shown to reduce the numbers of activated microglia associated with a lower plaque burden7 and a modest reduction in soluble amyloid beta levels.8 Consistent with these experimental studies, this pilot study demonstrated that pioglitazone resulted in cognitive and metabolic improvements in patients with AD and MCI with DM. The reason for these benefits is not fully determined. Despite the small sample size, the results suggest that pioglitazone may offer a novel strategy for the treatment of AD and MCI with DM. Larger double-blind, randomized, placebo-controlled studies are needed to confirm these results. Financial Disclosure: The authors state that they have no financial disclosures to declare. There are no conflicts of interest in this letter. Author Contributions: Haruo Hanyu: study concept and design, acquisition of subjects and data, analysis and interpretation of data, and preparation of manuscript. Tomohiko Sato, Akihiro Kiuchi, Hirofumi Sakurai, and Toshihiko Iwamoto: acquisition of subjects and data analysis. Sponsor's Role: None.