Evaluation of the possibility of estimating therapeutic response to Donepezil in patients with dat using ezis

Purpose: Donepezil hydrochloride (Donepezil) is used clinically for the symptomatic treatment of dementia of Alzheimer type (DAT). DAT is characterized by progressive impairment of cognitive function and memory. associated with loss of presynaptic cholinergic function. Cholinergic agents such as cholinesterase inhibitors or cholinergic agonists are expected to have the potential to improve these symptoms. Donepezil is a piperidine-based acetylcholinesterase and acts by blocking cholinesterase. Donepezil can improve symptoms in patients with mild-to-moderate DAT and is not effective for all patients with DAT. Side effects such as nausea, vomiting and diarrhea sometimes occur with it. Estimation of therapeutic response to Donepezil before the start of treatment is anticipated. Brain perfusion single photon emission computed tomography (SPECT) is a functional imaging diagnosis method, and decrease in regional cerebral blood flow (rCBF) in brain regions affected by DAT is measured by SPECT. Visual diagnosis and quantitative analysis by region of interest (ROI) have been widely used as a conventional method for evaluation of brain SPECT images. ROI analysis has problems such as poor reproducibility and lack of objectivity in analysis of lesions randomly selected by operators, Recent methods of three-dimensional statistical imaging analysis such as statistical parametric mapping (SPM), three-dimensional stereotactic surface projection (3DSSP) and the easy Z-score imaging system (eZIS) have excellent in objectivity and reproducibility, due to automatic brain standardization and statistical processing of data from the entire brain. Their usefulness in detecting abnormalities in the brain of patients with DAT has been illustrated in many reports. SPM with voxel-by-voxel analysis using Student's unpaired t-test and paired t-test in the stereotactic space of the entire brain has high specificity but low sensitivity in detecting abnormalities. 3DSSP using Z-values has both high sensitivity and specificity in detection, but it is difficult to obtain three-dimensional spatial information of abnormalities from surface projection images. eZIS is a new statistical imaging analysis system permitting brain standardization using SPM and statistical analysis of the entire brain using Z-values. In this study, we examined the possibility of estimating therapeutic response to Donepezil in patients with DAT using eZIS. Methods: Eighteen patients (5 men, 13 women, age range, 66-83 years old; mean age, 73.6 years old) who complained of memory impairment were recruited from an outpatient dementia clinic of the Department of Neuro psychiatry of Osaka City University Hospital, between 2001 and 2003. The clinical diagnosis of DAT was based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The patients received daily oral doses of Donepezil (5 mg/d). Each patient underwent the Alzheimer's Disease Assessment Scale Japanese edition (ADAS-Jcog) test, a recognition function test, and baseline SPECT examination at the time of initial evaluation and was clinically followed by a second ADAS-Jcog test and SPECT examination 12 weeks later. Informed consent of each patient was obtained after a detailed explanation concerning this study before beginning treatment. Before SPECT scanning was performed, an intravenous line was established in the right cubital vein of all patients while they were supine with their eyes closed. Each patient received a 740-MBq intravenous injection of Tc-99m-ethyl cysteinate dimer (ECD). Dynamic data were collected (70 x 1-s frame images) simultaneously with the injection using a large field of view encompassing the cranial and thoracic regions. Thirty minutes after injection of Tc-99m-ECD, brain SPECT imaging was performed with a 128 x 128 pixel matrix in step and shoot mode and with a triple-head SPECT system (GCA 9300 A/HG, Toshiba Medical Systems, Inc., Tokyo, Japan). All subsequent image manipulation and data analysis were performed by the eZIS software, which was developed by Dr.Matsuda ( National Center Hospital for Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry) on a Windows-2000-based personal computer. The eZIS software in our hospital has two processes; the first is spatial normalization of the SPECT images using SPM 99 software processes, and the second is measurement of Z-values for the entire brain by comparison with a control database constructed from SPECT images of 38 control patients in our hospital. When Z-values for each side of the posterior part of the cingulate gyrus, parietal lobe, the posterior part of the temporal lobe and hippocampus are greater than 4, 2 points are scored. When the Z-values are more than 2 and less than 4, 1 point is scored. When the Z-values are less than 2, 0 point is scored. Finally, the total numbers of points for these 8 regions are compared with changes in the results of ADAS-Jcog tests before to after Donepezil medication. Results: The total scores for 9 patients in whom improvements in ADAS-Jcog tests were found ranged from 0 to 8 (mean 3.7). The total scores for the other 9 patients in whom improvement was not observed ranged from 5 to 11(mean 8.8). A significant difference (p<0.05) was recognized between these two groups (Mann-Whitney U-test). Conclusions: The possibility of estimating therapeutic response to Donepezil in patients with DAT using eZIS was demonstrated by our study.al application value.g agent. (authors)