A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutations.

An activating mutation of Fms-like tyrosine kinase 3 (FLT3) is the most frequent genetic alteration associated with poor prognosis in acute myeloid leukemia (AML). Although many FLT3 inhibitors have been clinically developed, no first-generation inhibitors have demonstrated clinical efficacy by monotherapy, due to poor pharmacokinetics or unfavorable safety profiles possibly associated with low selectivity against FLT3 kinase. Recently, a selective FLT3 inhibitor, quizartinib, demonstrated favorable outcomes in clinical studies. However, several resistant mutations emerged during the disease progression. To overcome these problems, we developed a novel FLT3 inhibitor, FF-10101, designed to possess selective and irreversible FLT3 inhibition. The co-crystal structure of FLT3 protein bound to FF-10101 revealed the formation of a covalent bond between FF-10101 and the cysteine residue at 695 of FLT3. The unique binding brought high selectivity and inhibitory activity against FLT3 kinase. FF-10101 showed potent growth inhibitory effects on human AML cell lines harboring FLT3 internal tandem duplication (FLT3-ITD), MOLM-13, MOLM-14, and MV4-11, and all tested types of mutant FLT3-expressing 32D cells including quizartinib-resistant mutations at D835, Y842, and F691 residues in the FLT3 kinase domain. In mouse subcutaneous implantation models, orally administered FF-10101 showed significant growth inhibitory effect on FLT3-ITD-D835Y- and FLT3-ITD-F691L-expressing 32D cells. Furthermore, FF-10101 potently inhibited growth of primary AML cells harboring either FLT3-ITD or FLT3-D835 mutation in vitro and in vivo. These results indicate that FF-10101 is a promising agent for the treatment of patients with AML with FLT3 mutations, including the activation loop mutations clinically identified as quizartinib-resistant mutations.

[Expectations toward the care service and the medical service for elderly in Japan].

AIM: With the purpose of gathering basic data in order to prompte various research toward the realization of a vibrant aging society, we performed a nationwide 'Survey on life' intended for citizens over 60 years old who engage in independent living, preserving their state of health even after retirement. METHODS: We created a survey form consisting of 14 question items. Processing 4,000 persons surveyed from 100 locations chosen nationwide, we obtained a total of 2,370 answers from both male and female subjects, with an effective recovery rate of 59.3%. We divided the respondents according to their age into four groups (group 1: 60-64 years; group 2: 65-69 years; group 3: 70-74 years; group 4: over 75 years), examined and analyzed them using multivariate statistical analysis followed by a summary of each response item. RESULTS: In the main aggregate results, the percentage living with a spouse indicated a double decrease in the 4th group of female respondents in comparison with male respondents, and together with that an increase of the living alone percentage identical with the one above could be seen. The subjective sense of health has gradually declined after peaking in group 1, while the number of persons complaining of poor health doubled as we moved to group 3 and group 4. Analysis of the factors that contribute to discrimination in each age category showed that health and economic items together with social participation items were extracted as the main determining factors. Economic anxiety is strong in group 1 and group 2, in particular, anxiety about the future life showed a tendency about two times higher in the female group rather than the male group of the same age category. The eagerness to contribute to society indicated a high tendency within the female group 1 and group 2. In the canonical correlation analysis of all age categories, the weight coefficient of physical anxiety and health anxiety within the male groups showed 1.95, respectively 2.52. On the other hand, economic anxiety and anxiety about future life indicated -1.97, respectively -1.70, showing large fluctuations on these four items. The female groups presented the same tendency. Items showing a high correlation with individual respondents, showed an increase of the wieght coefficients, starting with younger age, in the following order: 'state of health', 'mental and physical energy', 'desire to contribute to society', 'state of sleep', 'leasure activity', 'living with family', 'health anxiety', 'physical anxiety'. There was no distinction between male and female. Observing the aspects of the relative changes represented in the graphic in the order of the age category, searching for the avarage value of the weight coefficient of all individual respondents considering the four items that registered high fluctuations, within group 1 and group 2 under 70 years, the economic anxiety and anxiety about future life are strong, so that as we move to groups over 70 years, health and physical anxieties tend to emerge slowly. CONCLUSIONS: The result of this survey suggested that for senior citizens, through all age categories, economic and health anxieties existing at various levels and under different aspects, will soon bring a large strain upon the mind of the elderly, turning into the main negative background factor which leads to a general decline of the mental health and the body, and what is more, the willingness to be active.

Synthesis of dimethyl gloiosiphone a by way of palladium-catalyzed domino cyclization.

The synthesis of a spiro[4.4]nonane skeleton by the palladium-catalyzed domino cyclization of a linear 7-methylene-2,10-undecadienyl acetate is described. The pi-allylpalladium intermediate underwent intramolecular alkene insertion with high intraannular diastereoselectivity, followed by intramolecular Heck-type cyclization, leading to a spiro[4.4]nonane system. Oxidation of the allylic ether moiety and transformation of the vinyl group to an exo-methylene unit provided 3, which is the known synthetic intermediate of dimethyl gloiosiphone A (2).

[Treatment of bedsores--combination of therapies depended the experimental design method].

The treatment of bedsores is a particular problem in geriatric medicine. We selected standard drugs that may be effective for the decubitus ulcer, and investigated combination therapy to develop efficient treatment The subjects were 16 patients in whom the grade of the bedsore was evaluated as II to IV according to the Shea's depth classification. Treatment was performed while all patients were on air mats. We selected drugs and treatment methods based on the previously established experimental design of Taguchi. Based on this, we created and adapted 16 different component combination treatment programs in accordance with the L16 rectangular cross table. The following component factors were adopted: A: types of covering substances on the wound surface (Elase ointment, isodine sugar, isodine gel solcoseryl ointment); B: Isalopan powder; C: Spray of 10 ml physiological saline containing 500 microg of prostaglandin (concentration 0.005%); D: daily number of treatments; and F: presence or absence of tapping. We serially measured the wound surface area as an index of the speed of wound healing, and measured the interval (day) until the area decreased to one half of the original size (T1/2, half life). We analyzed data on one combination treatment each in 16 patients. Analysis of variance of the above factors showed significant F values for factors A, B, D and F. The contribution rates for factors A, B, D and F were 37.84%, 8.47%, 14.98% and 13.81%, respectively. The error term (e) was 16.37%. Optimal results were seen in the groups in which solcoseryl ointment had been applied twice a day. In this study, prostaglandin, which had been anticipated to be effective, did not show any effects. The error term (e) suggests the presence of other healing factors including individual differences. Concerning this point, it well be necessary to examine a larger number of patients in the future. With ointment treatment alone, without using an air mat, it was confirmed that bedsore area reduction was extremely unstable. Decompression of the affected part may be a basic prevention factor and essential treatment of bedsores.

Prognostic implications of swallowing ability in elderly patients after initial recovery from stroke.

BACKGROUND: It remains unclear how swallowing assessment can help clinicians to predict the risk for pneumonia in elderly persons after ischemic stroke. A prospective case-control study was conducted to evaluate the prognostic utility of swallowing ability assessments. METHODS: Participants were 136 elderly persons who had an acute ischemic stroke 3-12 months previously. They were separated into four groups based on their history of repeated episodes of pneumonia in combination with swallowing ability: Group 1 had neither repeated pneumonia nor swallowing abnormality (n = 69); group 2 had repeated pneumonia but no swallowing abnormality (n = 0); group 3 had swallowing abnormality but no repeated pneumonia (n = 54); and group 4 had both swallowing abnormality and repeated pneumonia (n = 13). The follow-up period was as long as 2.2 years. Outcomes and causes of death were compared among the groups. RESULTS: During the study, the overall mortality rate was higher in group 3 (24 deaths, 44.4%) and group 4 (9 deaths, 69.2%) than in group 1 (3 deaths, 4.3%, both p <.05). The annual mortality rate from pneumonia was also significantly higher in group 3 (21.2%) and group 4 (38.2%) than in group 1 (0.8%, p <.0001). The odds ratio for patients who subsequently died of pneumonia was 46.8 between groups 1 and 3. CONCLUSIONS: The high sensitivity (.96) and specificity (.68) of swallowing ability indicate that the method is useful for identifying those persons at greatest risk for pneumonia and death after ischemic stroke.

Aspiration and infection in the elderly : epidemiology, diagnosis and management.

Aspiration of the oropharyngeal or gastric contents by elderly persons often leads to lower respiratory tract infections, such as aspiration pneumonia or pneumonitis. The existence of dysphagia and aspiration in elderly patients are important factors in the occurrence of aspiration pneumonia, but are not sufficient to cause aspiration pneumonia in the absence of other risk factors. Salivary flow and swallowing can eliminate Gram-negative bacilli from the oropharynx in healthy persons. However, elderly persons may have diminished production of saliva as a result of medications and oral/dental disease, leading to poor oral hygiene and oropharyngeal colonisation with pathogenic organisms. When dysphagic patients aspirate pathogenic bacteria while swallowing food or liquids, they must also have decreased defences, such as impaired immunity or pulmonary clearance, in order to develop aspiration pneumonia.Elderly patients with cerebrovascular disease often have dysphagia that leads to an increased incidence of aspiration. It was previously reported that patients with silent cerebral infarction affecting the basal ganglia were more likely to experience subclinical aspiration and an increased incidence of pneumonia. Basal ganglia infarction leads to the impairment of dopamine metabolism and, as a consequence, a decrease of substance P in the glossopharyngeal nerve and sensory vagal nerves. Therefore, dysphagia and a decreased cough reflex may be induced by the impairment of dopamine metabolism in some elderly patients with cerebrovascular disease, suggesting that pharmaceutical agents which modulate dopamine metabolism may be able to improve swallowing and the cough reflex in patients with basal ganglia infarction. The main strategy for controlling aspiration and aspiration-related pulmonary infection in the elderly is to prevent aspiration of pathogenic bacteria along with the oropharyngeal or gastric contents. Because aspiration pneumonia in the elderly is related to certain risk factors, including dysphagia and aspiration, effective preventive measures involve various approaches, such as pharmacological therapy, swallowing training, dietary management, oral hygiene and positioning.

Immunolocalization of 14-3-3 isoforms in brains with Pick body disease.

Immunolocalization of 14-3-3 protein isoforms in relation to Pick bodies in Pick body disease (PBD) brains was investigated. Weakly granular immunoreactivity of 14-3-3 proteins was found in neurons in control subjects and in Pick body disease brains. In addition to this granular immunoreactivity, many Pick bodies were immunopositive for 14-3-3 proteins as confirmed with double-immunofluorescence with an anti-PHF tau (AT8) and anti-14-3-3 that recognizes all its isoforms (common). When probed with isoform-specific antibodies, Pick bodies were positive for beta, gamma, epsilon, eta, tau, and zeta isoform and exhibited immunostaining pattern similar to that observed with the anti-14-3-3 proteins (common). In addition, immunoreactivity of sigma isoform, so far considered to be exclusively extraneuronal, was unexpectedly found in Pick bodies, normal hippocampal neurons and brain homogenate from age-matched controls. Although localization of 14-3-3 proteins in Pick bodies suggests their involvement in Pick body formation, their role may be variable dependent on the isoforms differently expressed in different area in the brain.

[Severe chlamydia pneumoniae pneumonia requiring mechanical ventilation and steroid therapy in an elderly patient].

A 75-year-old man first developed dyspnea and low-grade fever in late March. A chest X-ray film showed infiltration in the right lower lung field and blood gas analysis revealed severe hypoxemia. Accordingly, he was diagnosed as having pneumonia and was admitted to our hospital on March 11, 2003. Mechanical ventilation for progressive respiratory failure was started immediately after admission, and he was treated with antibiotics. Chlamydia pneumoniae pneumonia was diagnosed due to an increase of the Chlamydia pneumoniae antibody titer. He had prolonged respiratory failure despite antibiotic therapy. Therefore, steroid therapy was started on day 15 for respiratory failure. At 21 days after admission, the infiltration was found to be decreased on chest X-ray films and improvement of hypoxemia allowed extubation. In conclusion, when severe community-acquired pneumonia occurs in elderly patients, we should remember the possibility of atypical pneumonia such as that due to Chlamydia pneumoniae infection.

Differences in regional cerebral blood flow patterns in male versus female patients with Alzheimer disease.

BACKGROUND AND PURPOSE: There may be some differences in the pathophysiology between men and women with Alzheimer disease (AD). This study was undertaken to explore the possible influence of sex on regional cerebral blood flow (rCBF) patterns in patients with AD. METHODS: Single photon emission CT (SPECT) was performed in 30 men and 30 women with AD, and the SPECT data were analyzed by using 3D stereotactic surface projections. RESULTS: There were no significant differences in age, duration of disease, years of education, cognitive deficits and patterns, and MR imaging findings (grade of brain atrophy and extent of white matter hyperintensity lesions) between the two groups. Both male and female patient groups showed decreased rCBF patterns in the parietotemporal lobe, posterior cingulate cortex, and precuneus, which are considered to be the characteristic SPECT findings of AD. There were, however, some differences in rCBF patterns: men had a more severe decrease of rCBF in the parietal and posterior cingulate cortex, whereas women had a more severe decrease of rCBF in the medial temporal region and frontal lobe. CONCLUSION: These data provide evidence that patterns of rCBF deficits differ between the sexes, a finding that supports the concept of heterogeneity of the underlying pathophysiology of AD.

Metabolism of pyrogallol to purpurogallin by human erythrocytic hemoglobin.

The aim of this study was to investigate the oxido-reductive reactions of human hemoglobin with pyrogallol and the metabolism of pyrogallol by the protein, which contains a protoporphyrin IX like cytochrome P-450. Pyrogallol, having three hydroxy groups at the adjacent positions in the benzene ring, oxidized human oxyhemoglobin to methemoglobin and reduced human methemoglobin to oxyhemoglobin. Since superoxide dismutase and catalase inhibited these reactions extensively, active oxygens such as superoxide and hydrogen peroxide were considered to be involved in the oxido-reductive reaction of human hemoglobin by pyrogallol. It was also found that the metabolism of pyrogallol to purpurogallin occurred quickly in human erythrocytes, i.e., when pyrogallol was added to human erythrocyte suspension, it oxidized intracellular hemoglobin and produced purpurogallin. The metabolism of pyrogallol to purpurogallin was explained by the pyrogallol oxidation with superoxide and hydrogen peroxide produced during the oxido-reductive reactions of human hemoglobin with pyrogallol. The present results show that human erythrocytes can metabolize pyrogallol, suggesting that the cells may be involved in the metabolism of some drugs in the human body.

14-3-3 proteins and zeta isoform containing neurofibrillary tangles in patients with Alzheimer's disease.

Immunolocalization of 14-3-3 proteins in Alzheimer's disease (AD) brains was investigated using isoform-specific antibodies. Weak granular immunoreactivity of 14-3-3 proteins was found in neuronal cytoplasm in control subjects and AD brains. Both intracellular and extracellular neurofibrillary tangles (NFTs), as well as neuropil thread-like structures, were immunopositive for 14-3-3 proteins. This was corroborated by triple-fluorolabeling method visualizing paired helical filament (PHF) tau and 14-3-3 epitopes in relation to fibrillary state detected by thiazin red. Pretangle neurons (positive for PHF-tau without fibrillary structure detected by thiazin red) only contained fine granular immunoreactivity (IR) of 14-3-3, which was similarly found in unaffected neurons. Granular cytoplasmic IR of 14-3-3 proteins in pretangle neurons was not colocalized to granular tau-like IR, which suggests that participation of 14-3-3 proteins in NFT formation was restricted to its later stages. Its zeta isoform was most prominent in these NFTs, suggesting that this isoform is a major component involved in the formation of NFTs. In contrast, IR of epsilon isoform was found in the neuropil of the hippocampus and that of sigma isoform was localized to granule cells of the dentate gyrus in AD brains, as seen in the age-matched controls. Expression of 14-3-3 proteins were found to be highly variable and dependent on their isoforms, regions and cell types. Molecular, as well as topographical, dissection of 14-3-3 proteins will provide us with an improved understanding of this molecule in normal and pathological conditions.

Cerebral blood flow patterns in Binswanger's disease: a SPECT study using three-dimensional stereotactic surface projections.

We investigated regional cerebral blood flow (rCBF) patterns in Binswanger's disease (BD) patients using single photon emission computed tomography (SPECT). SPECT data on 22 patients with BD were analyzed using three-dimensional stereotactic surface projections (3D-SSP) and were compared with those of 22 patients with Alzheimer's disease (AD). rCBF patterns in patients with BD were different from those with AD. The BD group had greater CBF reduction in the frontal and anterior cingulate cortices, while the AD group had greater CBF reduction in the temporoparietal and posterior cingulate cortices. However, the rCBF pattern of each patient was more variable, and could be divided into three patterns: anterior cerebral hypoperfusion, posterior cerebral hypoperfusion, and diffuse cerebral hypoperfusion patterns. A distinct CBF reduction in the temporoparietal and/or posterior cingulate cortices, indistinguishable from the CBF pattern observed in AD, was demonstrated in 8 of 22 (36%) patients with BD, in particular there was bilateral hemispheric involvement with a diffuse hypoperfusion pattern. Although no pathological confirmation could be performed, some of the BD patients with CBF reduction in the posterior cerebral cortices may represent additional changes in the brain due to AD. In the future, a longitudinal study including pathology will be needed to determine whether these patients have coexisting AD pathology.

Effects of partial volume correction on discrimination between very early Alzheimer's dementia and controls using brain perfusion SPECT.

We assessed the accuracy of brain perfusion single-photon emission computed tomography (SPECT) in discriminating between patients with probable Alzheimer's disease (AD) at the very early stage and age-matched controls before and after partial volume correction (PVC). Three-dimensional MRI was used for PVC. We randomly divided the subjects into two groups. The first group, comprising 30 patients and 30 healthy volunteers, was used to identify the brain area with the most significant decrease in regional cerebral blood flow (rCBF) in patients compared with normal controls based on the voxel-based analysis of a group comparison. The second group, comprising 31 patients and 31 healthy volunteers, was used to study the improvement in diagnostic accuracy provided by PVC. A Z score map for a SPECT image of a subject was obtained by comparison with mean and standard deviation SPECT images of the healthy volunteers for each voxel after anatomical standardization and voxel normalization to global mean or cerebellar values using the following equation: Z score = ([control mean]-[individual value] )/(control SD). Analysis of receiver operating characteristics curves for a Z score discriminating AD and controls in the posterior cingulate gyrus, where a significant decrease in rCBF was identified in the first group, showed that the PVC significantly enhanced the accuracy of the SPECT diagnosis of very early AD from 73.9% to 83.7% with global mean normalization. The PVC mildly enhanced the accuracy from 73.1% to 76.3% with cerebellar normalization. This result suggests that early diagnosis of AD requires PVC in a SPECT study.

Long-term effects of lipoprotein(a) on carotid atherosclerosis in elderly Japanese.

BACKGROUND: Serum level of lipoprotein(a) [Lp(a)] is hereditarily constant throughout life within an individual, but the relationship between Lp(a) and atherosclerosis in elderly people is still controversial. METHODS: Serum Lp(a) levels were studied in 208 elderly Japanese participants aged 80 years with a variety of diseases, using carotid ultrasonography (US), brain computerized tomography (CT), electrocardiography (ECG), and ankle brachial pressure index (ABPI). Carotid plaque lesions were divided into 3 types based on the US echogenicity assessed by a computer-assisted system: L type (hypoechoic plaque), H type (hyperechoic plaque), and M type (heterogeneous plaque). RESULTS: The frequency of the L type and occlusion was significantly higher in the high Lp(a) group (n = 38) than in the normal Lp(a) group (n = 170). The mean height of the plaque was also greater in the high Lp(a) group than in the normal Lp(a) group. There was no difference in CT findings between the two groups. Myocardial ischemia on ECG and low ABPI (<0.9) were both frequently, but not significantly, seen in the high Lp(a) group. Among factors influencing US findings, multiple regression analysis showed that high Lp(a) correlated markedly to L type and cigarette smoking correlated to M type. CONCLUSIONS: These findings indicate that, in Japanese elderly patients aged 80, serum Lp(a) strongly correlates with hypoechoic carotid lesions, which correspond histologically to lipid-rich, unstable atherosclerosis. This suggested that Lp(a) could promote the formation of atherosclerosis throughout life, and play a role as an independent risk factor for circulatory disturbance of the organ later in life.

[A case of anaplastic large cell lymphoma associated with Epstein-Barr virus infection, representing clinicopathological features of malignant histiocytosis].

An 82-year-old woman was admitted with fever and anorexia. Aggravated pancytopenia and liver dysfunction suggested the presence of disseminated intravascular coagulation. The serum ferritin level increased to 9,100 ng/ml. Bone marrow aspiration showed an increase of histiocytes with phagocytosis and a diagnosis of hemophagocytic syndrome was made. Symptomatic therapy was performed because of her deteriorated general condition. She died of multiple organ failure, 32 days after admission. Autopsy revealed swollen lymph nodes with proliferation of large neoplastic cells containing rich cytoplasm and pleomorphic and multi-segmented large nuclei. The immunophenotype of the neoplastic cells was LCA-, CD3-, CD5-, CD 20-, CD79a-, UCHL1-, MT1-, CD15-, p80-. Neoplastic cells were positive for CD30, mainly in Golgi apparati, and also positive for EBV-encoded small nonpolyadenylated RNAs (EBER). This case was diagnosed as anaplastic large cell lymphoma (ALCL) associated with hemophagocytic syndrome. It was estimated that Epstein-Barr virus had played an important role in the development of ALCL in the present case.

[Characteristics of MRI features in Alzheimer's disease patients predicting response to donepezil treatment].

We attempted to investigate whether morphological features as shown on magnetic resonance imaging (MRI) predict response to donepezil treatment in patients with Alzheimer's disease (AD). Sixty-three patients with AD were divided into responders (n = 16) and non-responders (n = 47) based on the changes in the MMSE score between baseline and endpoint. Atrophy of the substantia innominata was more pronounced in responders than non-responders. Although no significant difference in the medial temporal lobe atrophy between responders and non-responders was found, magnetization transfer ratios (MTRs) of the hippocampus and parahippocampus, indicators of structural damage, in the non-responder group were significantly reduced compared to those in the responder group. There were no significant differences in the severity of white matter lesions between the two groups. Logistic regression analysis revealed that the overall discrimination rate was 81%, with 85% of non-responders and 69% of responders, through measurement of the thickness of the substantia innominata and MTR of the hippocampus and parahippocampus. These results suggest that AD patients who show more severe cholinergic dysfunction and less severe structural damage of the hippocampus and parahippocampus as shown on MRI are likely to respond to donepezil treatment.

[Marked decrease of intracranial atherosclerosis in contrast with unchanged coronary artery stenosis in Japan].

We conducted comparative studies on intracranial atherosclerosis and coronary artery stenosis over the past 28 years. Two-year consecutive autopsy case studies from an urban geriatric hospital between 1974-1975 (Group I. 484 cases). 1986-1987 (Group II, 504 cases) and 2000-2001 (Group III, 273 cases) were employed. Atherosclerotic changes of the bilateral middle cerebral arteries and basilar artery were semiquantitatively evaluated as none (0), mild (1), moderate (2) and severe (3) and values of the 3 arteries were totalled to give a value of 0-9 which was taken as the intracranial atherosclerotic index (ICAI). The coronary stenotic index was calculated as previously reported (Sugiura et al 1969). ICAI and CSI were directly compared with each other, together with risk factors for each, including mean blood pressure (BP), serum level of total cholesterol (Tch) and the history of diabetes mellitus (DM+). Chronologically ICAI decreased dramatically but CSI did not change at all. There was continuous lowering of BP, elevation of Tch and increased incidence of DM+. There was a significant positive correlation in BP in relation to both ICAI and CSI (p < 0.01). DM+ vs. CSI (p < 0.01) and ICAI (p < 0.05), and Tch vs. CSI (p < 0.01) but not ICAI. Regression analysis highlighted age and BP as major risk factors for ICAI. Our study provides the first morphological confirmation of marked decrease of the intracranial atherosclerosis in the recent 28 years, in contrast with unchanged coronary stenosis in Japanese elderly subjects.

Atrophy of the substantia innominata on magnetic resonance imaging predicts response to donepezil treatment in Alzheimer's disease patients.

To investigate whether atrophy of the substantia innominata as shown on magnetic resonance imaging (MRI), reflecting degeneration of cholinergic neurons in the nucleus basalis of Meynert, predicts response to donepezil treatment in patients with Alzheimer's disease (AD), we studied correlations between the thickness of the substantia innominata and clinical efficacy. Eighty-two patients were divided into responders, including transiently and continuously responding groups, and nonresponders, based on the changes in the Mini-Mental State Examination (MMSE) score from baseline at 3 months and at 12 months. Atrophy of the substantia innominata was more pronounced in transiently and continuously responding groups than nonresponders, but no significant change in the thickness between transiently and continuously responding groups was found. The MMSE score changes from baseline at 3 months and at 12 months significantly inversely correlated with the thickness of the substantia innominata. Logistic regression analysis revealed that the overall discrimination rate with the thickness of the substantia innominata was 70% between responders and nonresponders. We conclude that atrophy of the substantia innominata on MRI helps to predict response to donepezil treatment in patients with AD.

Apolipoprotein E genotype and early Alzheimer's disease: a longitudinal SPECT study.

BACKGROUND AND PURPOSE: To determine the association of the apolipoprotein E (APOE) genotype and longitudinal changes of regional cerebral blood flow (rCBF) in Alzheimer's disease (AD). Previous reports have yielded conflicting results concerning this association. METHODS: A retrospective cohort study was performed. rCBF was noninvasively measured using 99mTc-ethyl cysteinate dimer single-photon emission computed tomography in 23 patients with probable AD at the very early stage and at a mean interval of 24 months, as well as in 55 age-matched healthy volunteers. Patients were classified into 2 groups according to the presence of the epsilon 4 allele: 11 epsilon 4 carriers and 12 noncarriers. Correction for partial volume effects (PVEs) was performed in all patients using gray matter volume measured by magnetic resonance imaging. Statistical parametric mapping was used for the analysis of absolute rCBF data and the adjusted rCBF images of relative flow distribution. RESULTS: In the baseline study, both carriers and noncarriers showed significant decreases of absolute and adjusted rCBF in the psoterior cingulate gyri and precunei. After PVE correction, carriers showed a greater spread of areas with significant rCBF reduction from the parietotemporal to the frontal area than noncarriers during the follow-up period compared to healthy volunteers. Moreover, carriers showed a significant decline of absolute rCBF in the frontal cortex from the baseline to the follow-up study. CONCLUSIONS: The authors' study suggests that the APOE epsilon 4 allele is associated with the faster progression of AD, and PVE correction may be necessary for accurate assessments of SPECT studies of AD.