Brain perfusion follow-up in Alzheimer's patients during treatment with acetylcholinesterase inhibitors

Abstract

Transient cognitive and behavioral stabilization of patients with Alzheimer's disease (AD) is the main goal of long-term acetylcholinesterase inhibitor (AChEI) therapy, but response to treatment is variable and, indeed, only some of the patients are stabilized. This is usually assessed by means of clinical and neuropsychologic scales, whereas functional neuroimaging could allow objective evaluation of the topographic correlates of the effect of therapy on brain functioning. The aim of this study was to evaluate brain perfusion changes by SPECT in AD patients during chronic AChEI therapy in relation to their cognitive evolution.

Methods: Forty-seven consecutive outpatients with mild-to-moderate probable AD (as defined by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association and the Diagnostic and Statistical Manual of Mental Disorders [4th edition criteria] and a score of > or =15 on the Mini-Mental State Examination [MMSE]) were enrolled in 2 centers over a 1-y period and underwent SPECT with 99mTc-hexamethylpropyleneamine oxime at the time of enrollment (t(0)). All of them started AChEI therapy. Nine patients were lost at follow-up, and drugs were withdrawn from 3 patients. Of the remaining 35 patients, who received regular AChEI therapy (donepezil, 5 or 10 mg/d; rivastigmine, 6 or 9 mg/d) throughout the observation period, only the 31 patients receiving donepezil were considered to avoid the possible confounding effect of different drugs. The 31 patients completed the study and a second SPECT examination was performed 15.0 +/- 3.0 mo later (t(1)). They were divided into stabilized (17 patients) and nonstabilized (14 patients) subgroups on the basis of the minimum expected annual rate of decline of the MMSE score, derived from a meta-analysis of the literature. SPECT data were analyzed by means of statistical parametric mapping.

Results: At baseline, the stabilized and nonstabilized patients were comparable for age, sex distribution, education, MMSE scores, memory impairment (selective reminding test [SRT]), apolipoprotein E genotype, AChEI dose regimen, and SPECT findings. The SRT scores decreased significantly (P < 0.01) in the nonstabilized subgroup but not in the stabilized subgroup. No significant difference was found between the baseline and repeated SPECT data in the stabilized subgroup. In contrast, in the nonstabilized subgroup a significant perfusion reduction was found in the frontal, temporal, and parietal superficial cortex and in the occipital precuneus in the right hemisphere and in the frontal and mesial temporal cortex in the left hemisphere. On repeated SPECT, regional cerebral blood flow was significantly lower in a left frontal region in the nonstabilized group than in the stabilized group.

Conclusion: The regional cerebral blood flow decreases in several cortical regions in AD patients with cognitive deterioration despite long-term AChEI therapy, similar to that observed in untreated patients, whereas it remains stable in AD patients with stabilized cognitive performance during therapy.