Quantitative comparison of the bolus and steady-state methods for measurement of cerebral perfusion and oxygen metabolism: positron emission tomography study using 15O-gas and water.

To evaluate a new simplified bolus method for measurement of cerebral perfusion and metabolism, the parametric images with that method were compared with those obtained from the conventional steady-state method with 15O-gas. The new method also provided images of arterial blood volume (V0), which is a different parameter from cerebral blood volume (CBV) obtained using a C15O technique. Seven healthy volunteers and 10 patients with occlusive cerebrovascular diseases underwent positron emission tomography (PET) scans with both methods. Three-weighted integration was applied to calculate regional cerebral blood flow (rCBF) and regional cerebral metabolic rate of oxygen (rCMRO2) in the bolus method. Global and regional CBF and CMRO2 in volunteers were compared between the two methods and used as control data. Regional values in patients also were evaluated to observe differences between the bilateral hemispheres. Both rCBF and rCMRO2 were linearly well correlated between the two methods, although global difference in CMRO2 was significant. The difference in each parametric image except for V0 was significant between the bilateral hemispheres in patients. The bolus method can simplify oxygen metabolism studies and yield parametric images comparable with those with the steady-state method, and can allow for evaluation of V0 simultaneously. Increase in CBV without a change in V0 suggested the increase might mainly be caused by venous dilatation in the ischemic regions.

Comparison of the pattern of atrophy of the corpus callosum in frontotemporal dementia, progressive supranuclear palsy, and Alzheimer's disease.

OBJECTIVES: The loss of the neurons in layer 3, one of the groups of cortical neurons most vulnerable in various degenerative brain diseases, results in axonal degeneration leading to atrophy of the corpus callosum. Previous studies showed callosal atrophy in three degenerative dementias: frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD). However, it is unclear whether a characteristic pattern of atrophy is present in each. The objective of this study was to investigate whether the pattern of the callosal atrophy was different among patients with FTD, PSP, or early onset AD. METHODS: Eleven patients with FTD, nine patients with PSP, 16 patients with early onset AD, and 23 normal controls, all age and sex matched, were studied using MRI. The ratios of midsagittal corpus callosum areas to the midline internal skull surface area on T1 weighted images were analyzed. The corpus callosum was divided into quarters: the anterior, middle-anterior, middle-posterior, and posterior portions. RESULTS: Compared with controls, all three patient groups had significantly decreased total callosal/skull area ratio. An analysis of covariance adjusted for the total callosal area/skull area ratio showed that the anterior quarter callosal/skull area ratio in FTD, the middle-anterior quarter area ratio in PSP, and the posterior quarter area ratio in AD were significantly smaller than those in the other three groups. CONCLUSION: Although atrophy of the corpus callosum is not specific to any degenerative dementia, the patterns of the atrophy are different among patients with FTD, PSP, or early onset AD. Differential patterns of callosal atrophy might reflect characteristic patterns of neocortical involvement in each degenerative dementia.

Corpus callosum atrophy in patients with leukoaraiosis may indicate global cognitive impairment.

BACKGROUND AND PURPOSE: The extent of white matter high-intensity lesions (WMLs) on T2-weighted MR images may be an indicator of cognitive impairment, especially impairment related to frontal lobe dysfunction. However, it is unclear whether the extent of WMLs is an independent predictor of cognitive impairment. In patients with extensive WMLs, atrophy of the corpus callosum may be an important predictor of global cognitive impairment. The purpose of this study was to investigate the relation of the extent of WMLs and callosal size with cognitive functions in a patient population with a wide range of extent of WMLs. METHODS: We studied 62 patients, aged 49 to 86 years, who underwent MRI because of neurological symptoms and were diagnosed as having lacunar stroke or no specific neurological disease: 28 with lacunar infarcts and 34 without. Multivariate analysis was used to test the independent predictive value of patient age, sex, educational level, other medical illness, lacunar infarct, corpus callosum area, and extent of WMLs with respect to scores of Mini-Mental State Examination or verbal fluency task. RESULTS: Only callosal size and age were significant independent predictors of the scores of the Mini-Mental State Examination, while only the extent of WMLs was an independent predictor of the score of the verbal fluency task. CONCLUSIONS: Callosal atrophy may be an important predictor of global cognitive impairment in patients with WMLs, whereas the extent of WMLs per se may be related to impairment of frontal lobe function independent of callosal atrophy.

Long-term changes of hemodynamics and metabolism after carotid artery occlusion.

OBJECTIVE: To investigate whether in selected patients with internal carotid artery (ICA) occlusion and initially normal oxygen extraction fraction (OEF) measured with PET, subsequent changes of cerebral hemodynamics and metabolism occur during long-term follow-up and, if so, whether the changes are associated with atrophy of the corpus callosum or subsequent ischemic strokes. BACKGROUND: The course of the changes in cerebral hemodynamics and metabolism after ICA occlusion remain unclear. After ICA occlusion, an increase in OEF may increase the risk of cerebral ischemia, and an increase in cortical ischemia would cause progression of callosal atrophy. METHODS: The authors used PET and MRI to examine twice seven medically treated patients with unilateral ICA occlusion and initially normal OEF at intervals ranging from 24 to 64 (mean +/- SD, 42 +/- 17) months. No intervening ischemic attacks occurred between the two examinations. RESULTS: In the hemisphere with ICA occlusion, OEF increased and blood flow decreased during follow-up. At the follow-up evaluation, abnormally increased OEF values were found in three patients, in whom ipsilateral ischemic strokes occurred during subsequent follow-up (18 +/- 6 months). A decrease in oxygen metabolism also occurred and was significantly correlated with the decrease of callosal size. CONCLUSIONS: These preliminary findings in a small, selected patient sample suggest that in patients with ICA occlusion and initially normal OEF, deteriorations of cerebral hemodynamics and metabolism during long-term follow-up may be associated with callosal atrophy or subsequent ischemic strokes.

Atrophy of the corpus callosum associated with a decrease in cortical benzodiazepine receptor in large cerebral arterial occlusive diseases.

OBJECTIVES: It remains controversial whether selective neuronal ischaemic change develops in patients with occlusion of the large cerebral arteries. Previous studies have shown atrophy of the corpus callosum with reduced cortical oxygen metabolism in large cerebral arterial occlusive diseases, which might be indirect evidence of loss of the neurons in cortical layer 3. Recent studies of patients with ischaemic cerebrovascular diseases have demonstrated reduced central benzodiazepine receptor (BZR) binding in the normal appearing cortical areas, which might be more direct evidence of changes of the neurons. Although pathophysiology of the decreased BZR is unclear, a decrease in the cortical BZR binding with neuronal loss would cause atrophy of the corpus callosum. The purpose of this study was to determine whether atrophy of the corpus callosum is associated with a decrease in cortical BZR binding in large cerebral arterial occlusive diseases. METHODS: Seven patients with occlusive diseases of the middle cerebral or internal carotid artery and only minor subcortical infarctions were studied. Single photon emission tomographic images of (123)I labelled iomazenil (IMZ) obtained 180 minutes after injection were analysed for BZR binding. The midsagittal corpus callosum area/skull area ratio (on T1 weighted magnetic resonance images) was compared with the cerebral IMZ uptake/cerebellar IMZ uptake ratio. RESULTS: Compared with 23 age and sex matched control subjects, the patients had significantly decreased callosal area/skull area ratio. The degree of corpus callosum atrophy was significantly and strongly (rho=0.99, p<0.02) correlated with that of the decreases in the mean cerebral cortical IMZ uptake ratio. CONCLUSION: Corpus callosum atrophy may occur in association with a decrease in cortical BZR binding in large cerebral arterial occlusive diseases. Corpus callosum atrophy with decreased cortical BZR binding might reflect cortical neuronal damage in large cerebral arterial occlusive diseases.

Brain arteriolosclerosis and hemodynamic disturbance may induce leukoaraiosis.

OBJECTIVE: To investigate whether internal carotid artery (ICA) occlusive disease-induced hemodynamic disturbance is associated with extensive white matter high-intensity lesions (WMLs) on T2-weighted MR images in the hemisphere with lacunar infarct in the basal ganglia. BACKGROUND: Hemodynamic disturbance in the brain with arteriolosclerosis may be one of the mechanisms by which ischemic injury induces extensive WMLs. METHODS: The authors used MRI and PET to study 21 patients with unilateral ICA occlusion or stenosis and lacunar infarct in the bilateral basal ganglia. In hemispheres with ICA disease, the association of WMLs with the mean hemispheric values of oxygen extraction fraction (OEF)-an index of hemodynamic compromise-measured with the 15O-labeled gas steady-state technique was analyzed. Twenty-five patients with ICA occlusive disease without lacunar infarct were studied as control subjects. RESULTS: In the hemispheres with ICA disease, patients with lacunar infarct had a significantly greater severity of WMLs than control subjects, although the mean hemispheric values of the OEF showed no significant difference. The severity of WMLs correlated significantly with the mean hemispheric values of the OEF in patients with lacunar infarct, but not in control subjects. Multivariate analysis revealed that lacunar infarcts and increased OEF were independent predictors of extensive WMLs, with lacunar infarcts the most heavily weighted factor. CONCLUSION: Internal carotid artery occlusive disease-induced hemodynamic disturbance is associated with extensive WMLs in hemispheres with lacunar infarct. Hemodynamic disturbance may contribute to the development of extensive WMLs, although brain arteriolosclerosis may be a major contributing factor.

[Cerebral hemodynamics and risk for recurrent stroke in symptomatic internal carotid artery occlusion].

PURPOSE: In internal carotid artery occlusion, patients with inadequate blood supply relative to metabolic demand (misery perfusion) may be at increased risk for cerebral ischemia. This study investigated whether patients demonstrating misery perfusion on positron emission tomography (PET) have a high risk of subsequent stroke in symptomatic internal carotid artery occlusion. METHODS: We prospectively evaluated the relationship between the regional hemodynamic status of cerebral circulation and the subsequent risk of stroke in 40 patients with symptomatic internal carotid artery occlusion who underwent PET. Patients were divided into two hemodynamic categories according to the mean hemispheric value of oxygen extraction fraction (OEF) in the hemisphere supplied by the artery with symptomatic disease: patients with increased OEF and those with normal OEF. All patients were followed with medical treatment until the recurrence of stroke or death for 3 years. RESULTS: The three-year incidence of ipsilateral ischemic strokes for patients with normal OEF and those with increased OEF were 1 of 34 and 3 of 6 patients, respectively. A significantly higher incidence of ipsilateral strokes was found in patients with increased OEF (Kaplan-Meier analysis and log-rank test; p < 0.001). Multivariate analysis with the Cox proportional hazards model demonstrated that increased OEF significantly increased stroke recurrence: the relative risk was 19.5 (95% CI, 2.0-188.6) for ipsilateral stroke. An increase in the absolute OEF value was a better predictor of recurrent ischemic stroke than an OEF asymmetry. CONCLUSION: These findings suggest that patients with symptomatic internal carotid artery occlusion and misery perfusion have a high risk for subsequent stroke. Thus, identification and optimal treatment of patients with misery perfusion may be essential in preventing stroke.

Significance of increased oxygen extraction fraction in five-year prognosis of major cerebral arterial occlusive diseases.

UNLABELLED: In major cerebral arterial occlusive diseases, patients with increased oxygen extraction fraction (OEF), which is measured with PET, may be at increased risk for cerebral ischemia. However, the clinical significance of increased OEF remains unclear. This study investigated whether increased OEF is an independent predictor of 5-y risk of subsequent stroke. METHODS: We prospectively evaluated the relationship between the regional hemodynamic status of cerebral circulation and the subsequent risk of stroke in 40 patients with symptomatic internal carotid or middle cerebral arterial occlusive diseases who underwent PET. Patients were divided into two hemodynamic categories according to the mean hemispheric value of OEF-in the hemisphere supplied by the artery with symptomatic disease: one group with increased OEF and one with normal OEF. All patients were followed for 5 y with medical treatment until the recurrence of stroke or death. RESULTS: During 5 y, 11 total and 9 ipsilateral ischemic strokes occurred. The incidences of all ischemic strokes in patients with increased OEF and in those with normal OEF were 5 of 7 and 6 of 33 patients, respectively. There were 4 ipsilateral ischemic strokes in patients with increased OEF and 5 in those with normal OEF. Kaplan-Meier analysis revealed that the risks of all stroke and ipsilateral ischemic stroke in patients with increased OEF were significantly higher than in those with normal OEF (log-rank test; P<0.0002 and P<0.0018, respectively). Multivariate analysis with the Cox proportional hazards model showed that increased OEF significantly increased stroke recurrence: the relative risk was 7.2 (95% confidence interval [CI], 2.0-25.5; P<0.005) for all stroke and 6.4 (95% CI, 1.6-26.1; P<0.01) for ipsilateral stroke. An increase in the absolute OEF value was a better predictor of recurrent ischemic stroke than was OEF asymmetry. CONCLUSION: These findings suggest that an increased OEF is an independent predictor of 5-y risk of subsequent stroke. Identification of patients with increased OEF may have clinical significance in preventing recurrent stroke.

Production of prostaglandins E1 and E2 by adult human red blood cells.

We showed that human adult red blood cells (RBCs) produce prostaglandin E1 (PGE1) and E2 (PGE2). RBCs that were mechanically stressed in the presence of extracellular Ca2+ by being injected rapidly through a fine needle produced PGE1 and PGE2 within 30 min after this mechanical stress. The amounts of PGE1 and PGE2 produced by 1 x 10(9) mechanically stressed RBCs were approximately 50 pg and 100 pg, respectively, which were determined in the cytosolic fraction from sonicated RBCs using a competitive enzyme immunoassay method. A Western blot analysis using anti-cyclooxygenase-2 antibody revealed a band at the 70-kDa position in the samples from RBCs producing PGE1 and PGE2. Treatment with 10 micrograms/mL indomethacin completely inhibited the productions of PGE1 and PGE2. The present results may indicate a new role of RBCs in microcirculation.

Membrane targeting of RecA during genetic transformation.

Recombination in prokaryotes and eukaryotes is mediated by the RecA family of proteins. Although the interactions between RecA and DNA are well studied, the cellular location of these interactions is not known. Using genetic transformation of Streptococcus pneumoniae as a model system, there was increased expression of a protein, colligrin, and RecA, products of the rec locus during genetic transfer. These proteins formed a complex and were found associated with the membranes of genetically competent cells. With immunoelectron microscopy and subcellular fractionation, we showed that the induction of competence led to the translocation of RecA and colligrin to the membrane and to the formation of clusters of RecA in a colligrin-dependent step. Based on the behaviour of colligrin and RecA during genetic exchange and the numerous proteins in prokaryotes and eukaryotes with domains similar to colligrin, we suggest that there may exist a family of proteins, which gathers macromolecules at specific sites in biological membranes.

Association between angiotensin converting enzyme gene polymorphism and clinical features in autosomal dominant polycystic kidney disease.

We investigated the association between angiotensin converting enzyme (ACE) gene polymorphism and clinical manifestations in 47 patients with autosomal dominant polycystic kidney disease (ADPKD). One-hundred, age- and sex-matched subjects with non-ADPKD served as the controls. ACE gene polymorphism was analysed using a GeneAnp kit. Renal size was determined by abdominal CT scan, by adding the longitudinal axis of each kidney. Incidence of extrarenal complication was also examined. Out of 47 patients, 24 patients (51%) were II, 18 (38%) ID and 5 (11%) DD type. The frequencies of the I and D alleles as well as the distributions of ACE genotypes in ADPKD did not differ from those in controls. The number of patients undertaking renal replacement therapy was 11 in II (46%), 6 (33%) in ID and 2 (40%) in DD genotype, respectively, that was not significantly different among the groups. The mean age of the initiation of renal replacement therapy did not vary among the three genotypes. The slopes of 1/serum creatinine did not differ between II and ID genotypes, whose initial serum creatinine levels ranged from 1.5 to 2.5 mg/dl. Renal size, blood pressure, and extrarenal complications including liver cysts and cardiac valvular disease were unrelated to the ACE genotypes. The present data suggested the irrelevance of ACE gene polymorphism in clinical manifestations in patients with ADPKD.

Aggressive non-Hodgkin's lymphoma with massive involvement of the right ventricle.

A 69-year-old women with malignant lymphoma (diffuse large:Working formulation) had associated with intracavital involvement of the right ventricle. The patient was referred to us for further examination with a diagnosis of heart failure. A tumor mass was detected by magnetic resonance imaging in the right ventricular outflow tract. While in the hospital the patient experienced cardiogenic shock due to neoplastic pulmonary embolism. The tumor was surgically resected and the patient was then treated with systemic chemotherapy. She went into complete remission and has continued in this state for six months. This case demonstrates that early diagnosis and intensive chemotherapy contribute to a good prognosis of patients with malignant lymphoma associated with massive involvement of a cardiac chamber. A review of the Japanese literature is presented.

A novel missense mutation (Asn5-->Ile) in lecithin: cholesterol acyltransferase (LCAT) gene in a Japanese patient with LCAT deficiency.

We identified a novel missense mutation in the lecithin:cholesterol acyltransferase gene in a new case of lecithin:cholesterol acyltransferase (LCAT) deficiency. The patient was a 64-year-old diabetic Japanese male who showed an extremely low level of serum high-density lipoprotein-cholesterol, corneal opacities, anemia, and proteinuria. Both the patient's LCAT activity and mass were markedly low. DNA sequence analysis of the LCAT gene showed an A-to-T transition at base 97 in exon 1, and predicted a change in asparagine to isoleucine at the 5th amino acid of the protein. Restriction analysis of polymerase chain reaction-amplified DNA using Ase I showed that the patient was homozygous for this mutation. Our results suggested that asparagine 5 was an important amino acid and substitution with isoleucine caused marked reduction of LCAT activity and mass, resulting in LCAT deficiency.