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.

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.

[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.

Molecular cloning and characterization of the mouse thymocyte protein gene.

Chicken thymocyte protein (cThy28) has recently been identified and implicated to be involved in apoptosis of avian lymphocytes, while its functional role remains undefined. To elucidate the role of Thy28, we have molecularly cloned the mouse Thy28 (mThy28) cDNA and clarified its genomic organization in the present study. The mThy28 cDNA encodes a 226 amino acid protein, whose sequence is highly conserved among bacteria, yeast and plants as well as vertebrates. Northern blot analysis revealed abundant expression of approximately 1 kb mRNA in testis, liver, brain and kidney with lower levels of the expression in thymus, spleen, heart and stomach. The mThy28 gene spans at least 7 kb of genomic DNA, and contains eight exons and seven introns. The 5'-flanking region of the mThy28 gene does not contain a typical TATA box, but contains a putative CCAAT box and presumably multiple transcription initiation sites. Potential Sp1, GATA-1, -2, -3, AP-1, and p300 binding sites were found in the 5'-flanking region of the mThy28 gene. The gene was mapped to mouse chromosome 9.

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.

Recovery of platelet function after withdrawal of cilostazol administered orally for a long period.

To clarify the recovery of platelet function after abrupt withdrawal of cilostazol, we studied platelet function and cilostazol concentration in elderly who received cilostazol, 100 mg twice a day (200 mg/day), for a long period. After interviewing the time of final cilostazol intake, platelet aggregability was determined with an aggregometer using four different concentrations of adenosine-5'-diphosphate as an inducer, which showed the grading curve (GC) type and platetet aggregatory threshold index (PATI). Serum cilostazol concentration was also determined by high-performance liquid chromatography. The GC type and PATI showed suppressed platelet function until 15 hours after withdrawal in half of patients. Bleeding time measured by the Simplate method was prolonged within 4 hours, but recovered by 12 hours after the withdrawal. Some serum cilostazol concentrations were still high 15 hours after withdrawal, while platelets were inhibited even in patients with low serum concentration of cilostazol. In the group receiving the drug for less than 6 months, PATI correlated with serum cilostazol concentration, but platelets in the long-term administration group (more than 48 months) were suppressed at the low serum cilostazol concentration. These findings indicated that platelet function recovered within 12-16 hours after withdrawal in these patients.

Changes in carotid atherosclerosis patterns detected by ultrasonography in Japanese elderly patients with aortic aneurysm.

To clarify current changes in the patterns of carotid atherosclerosis in Japan, carotid ultrasonographic findings in Japanese male patients with aortic aneurysm were compared between two groups examined in different periods. The first group was recruited from 42 consecutively examined patients in 1997, while the second group consisted of 40 consecutive patients from September, 2001 to January, 2002. Carotid lesions were analyzed by computer, and classified into three types based on the texture: echolucent, hyperechoic, and heterogeneous types. The mean age of the first group was 72 years, similar to that of the second group. In the first group, cigarette smoking was frequently noted, while the mean BMI was greater and IHD and CVD were frequent in the second group. Fifty carotid lesions were seen in each group. Severe stenosis and hypoechoic type lesions were more frequent in the second group than in the first group. These findings indicated that hypoechoic-type lesions, which are considered to be lipid deposition, hemorrhage, or loose fibrous tissue, and severe stenosis, were increased in the more recent group. This predicted that circulatory disturbance due to unstable atherosclerotic lesions may increase in the future among the elderly because carotid lesions reflect vascular change in other organs.

Abnormal incorporation and utilization of alpha-tocopherol in erythrocyte membranes of streptozotocin-induced diabetic rats.

Alpha-tocopherol is a well-known lipophilic-free radical scavenger that is mainly localized in biomembranes. In this study, we investigated the changes in the incorporation and utilization of alpha-tocopherol in erythrocyte membranes of streptozotocin-induced diabetic rats and the effects of insulin to control hyperglycemia on these changes. Diabetes was experimentally induced by the injection of streptozotocin (60 mg/kg, i.v.). Blood was collected to determine the concentrations of alpha-tocopherol and its oxidative metabolite (alpha-tocopherolquinone) in plasma or erythrocyte membranes after streptozotocin injection. In streptozotocin-induced diabetic rats, alpha-tocopherol concentrations were decreased in erythrocyte membranes and increased in plasma. The ratio of alpha-tocopherol in erythrocyte membranes to that in plasma, which reflects the incorporation of alpha-tocopherol into erythrocyte membranes, was dramatically decreased in streptozotocin-induced diabetic rats. Moreover, the ratio of alpha-tocopherolquinone to alpha-tocopherol in erythrocyte membranes, which reflects the utilization of alpha-tocopherol, was increased in streptozotocin-induced diabetic rats. These changes were prevented by insulin to control hyperglycemia. These findings suggest that the abnormalities in the incorporation and utilization of alpha-tocopherol in erythrocyte membranes of streptozotocin-induced diabetes can be restored to normal by insulin therapy to control hyperglycemia.

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

Atrophy of the substantia innominata on magnetic resonance imaging (MRI), reflecting degeneration of cholinergic neurons in the nucleus basalis of Meynert, may be an in vivo marker of cholinergic damage. We attempted to investigate whether the MRI features of the substantia innominata predict response to donepezil treatment in Alzheimer's patients. The thickness of the substantia innominata was measured on the coronal T2-weighted MRI through the anterior commissure. Seventy-two patients treated with donepezil were divided into the two groups (responders and non-responders) based on changes in Mini-Mental State Examination (MMSE) scores from baseline to study endpoint. Atrophy of the substantia innominata was more pronounced in responders than non-responders. There was a significant inverse correlation between thickness of the substantia innominata and MMSE changes. MRI analysis of the substantia innominata may be a simple and practical method for the selection of possible treatment responders.

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.

Cerebral microbleeds in Binswanger's disease: a gradient-echo T2*-weighted magnetic resonance imaging study.

We investigated the incidence and the number of microbleeds (MBs) on T2*-weighted gradient-echo magnetic resonance imaging in 30 Binswanger's disease (BD) patients with diffuse white matter lesions and a varying degree of lacunar infarction, 51 multiple lacunar stroke (MLS) patients with multiple lacunar infarction and no or mild white matter lesions, and 59 elderly controls. MBs were found in 23 (77%) patients with BD, 26 (51%) patients with MLS, and 5 (8%) controls, and the incidence and the number of MBs were significantly greater in the BD group compared with MLS and control groups. Patients with BD had a more widespread location of MBs. More specifically, MBs were commonly found in areas within or surrounded by white matter lesions of the patients with BD. When 81 patients from both the BD and MLS groups were analyzed, logistic regression analysis showed that number of lacunar infarct, severity of white matter hyperintensity, and use of antiplatelet agents were significantly associated with MBs. Patients with BD exhibited a high frequency and number of MBs, indicating advanced bleeding-prone microangiopathy within the brain, which should be taken into account in treatment and management.

MR analysis of the substantia innominata in normal aging, Alzheimer disease, and other types of dementia.

BACKGROUND AND PURPOSE: The substantia innominata can be visualized on coronal thin-section T2-weighted MR images. The purpose of this study was to investigate the morphologic changes of the substantia innominata in normal aging by using MR imaging and to determine whether the changes in this structure on MR images were specific to Alzheimer disease (AD). METHODS: The thickness of the substantia innominata was measured on the coronal T2-weighted image obtained through the anterior commissure in 39 healthy control subjects (age range, 25-86 y; mean age, 62 y); 39 patients with AD; and 36 patients with non-AD dementia, including vascular dementia, frontotemporal dementia, and Parkinson disease with dementia. RESULTS: In the control subjects, the thickness of the substantia innominata significantly decreased with age. Compared with age-matched control subjects, both patients with AD and patients with non-AD dementia had significant atrophy of the substantia innominata. The thickness of the substantia innominata significantly correlated with scores from the Mini-Mental State Examination in patients with AD but not in patients with non-AD dementia. CONCLUSION: MR analysis reveals age-related shrinkage of the substantia innominata. Atrophy of the substantia innominata, which reflects degeneration in the nucleus basalis of Meynert, is pronounced both in patients with AD and in those with non-AD dementia. MR imaging features in this structure may not be specific to AD.

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.

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.

Effect of age on regional cerebral blood flow patterns in Alzheimer's disease patients.

The purpose of this study was to explore the influence of age on regional cerebral blood flow (rCBF) patterns in patients with Alzheimer's disease (AD). Single photon emission computed tomography (SPECT) was performed in 79 patients with AD, including 31 younger and 48 older patients divided according to age at examination (<70 and > or = 70 years), and the SPECT data were analyzed using three-dimensional stereotactic surface projection. Although no significant differences in severity and duration of disease between the two groups were found, there were some differences in rCBF patterns. Patients with younger AD had a more severe decrease of rCBF in the parietotemporal and posterior cingulate cortex, while patients with older AD had a more severe decrease of rCBF in the medial temporal region and medial frontal lobe. This observer-independent analysis of SPECT data provides an objective assessment of cortical rCBF abnormalities in patients with AD and is useful in demonstrating the differences in rCBF patterns between younger and older 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.

Prognosis of the elderly with asymptomatic atherosclerotic plaques of the carotid arteries.

OBJECTIVE: To elucidate the prognosis of the elderly with neurologically asymptomatic atheromatous plaques of the carotid arteries. METHODS: A total of 228 subjects aged 60 years or older, examined by carotid ultrasonography and platelet aggregation test, were studied. They were divided into 3 groups based on plaque morphology: the no lesion group (n=110), the nodular plaque group (n=47), and the mural plaque group (n=71). Platelet aggregability was assessed as suppressed, normal, or accelerated. RESULTS: During the 4.0 years of mean follow-up period, 31 subjects died, and 16 of the deaths were due to vascular events such as cerebral infarction or ischemic heart disease. The annual mortality rate due to vascular events was 0.5% in the no lesion group, 1.4% in the nodular plaque group, and 4.1% in the mural plaque group, and Kaplan-Meier survival curve showed poor prognosis of the mural plaque group (logrank statistics: 12.8, Df=2, p=0.0017). According to the Cox proportional hazard model, a high hazard ratio (HR) was seen in the mural plaque group (5.3) and also the accelerated platelet aggregability group (4.0). CONCLUSION: These findings suggested that subjects with mural plaques and accelerated platelet aggregability, even when asymptomatic, have a poor prognosis due to vascular events. Antiplatelet therapy and exercise stress test for detecting coronary artery disease should be considered in these subjects.

Evaluation of B-mode ultrasonographic images of carotid lesions by computer analysis as compared with visual assessment.

To establish an objective method for evaluating the characteristics of carotid artery lesions by B-mode ultrasonography, we compared the reproducibility of computer analysis with that of visual evaluation. Using two different models of ultrasonograph, we evaluated B-mode ultrasonographic images of 100 carotid artery lesions in a blinded fashion by computer analysis and visual evaluation, two times at a 1-month interval. Another 35 lesions were simultaneously imaged by the two models of ultrasonograph and were evaluated visually and by computer analysis to examine the correlation between results. For visual evaluation, carotid artery lesions were divided into the following 3 types based on texture and relative echogenicity as compared with that of adjacent muscle tissue: heterogeneous, hypoechoic, and hyperechoic. For computer analysis, images were computerized by means of a scanner (using Adobe Photoshop software). The echogenicity of all pixels included in the lesion and adjacent areas of muscular tissue was measured, and the lesion was classified into the following 3 types based on the shape of histograms of echogenicity: mixed-echoic (M), hyperechoic (H), and lucent (L). The reproducibility of the results derived by computer analysis had a significantly higher coincidence coefficient (kappa = 0.89) than those derived by visual evaluation (kappa =0.68). The coincidence coefficient (kappa) of the same lesions depicted by two different models of equipment was 0.77 for computer analysis as compared with only 0.32 for visual evaluation. These findings indicate that computer analysis of histogram shape and lesion echogenicity can improve intra-sonographer and inter-equipment reproducibility in the evaluation of lesion echogenicity and texture.