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ABSTRACT: We studied the antitumor activity of 2-amino-4,4alpha-dihydro-4alpha,7-dimethyl-3H-phenoxazine-3-one (Phx), which was synthesized by the reactions of 2-amino-5-methylphenol with bovine hemoglobin, on human B cell lymphoblastoid cell lines, P3HR-1 and Raji derived from African Burkitt's lymphoma, and the human T cell lymphoblastoid cell line Molt-4. We also studied whether Phx might cause apoptosis and necrosis in these cells.
We evaluated cell viability and apoptosis and necrosis of the cells in the presence of Phx, by using agarose gel electrophoresis, flow cytometry, and fluorescence microscopy.
Phx suppressed the viability of P3HR-1, Raji, and Molt-4 cells, though the suppression patterns were different, i.e., Phx suppressed the viability of P3HR-1, Raji, and Molt-4 cells at higher concentrations, while the drug enhanced the viability of Raji cells, but not those of P3HR-1 and Molt-4 cells at lower concentrations. To investigate which type of cell death - apoptosis or necrosis - is induced by Phx, induction of DNA ladder, phosphatidylserine externalization, and propidium iodide-permeable cells were examined in Phx-treated cells. Although Phx did not induce DNA ladder formation, it induced the phosphatidylserine externalization and propidium iodide-permeable cells, suggesting that Phx caused a mixed type of cell death, both apoptosis and necrosis. The population of early stage apoptotic cells was dominant in Raji cells, and that of the late stage apoptotic/necrotic cells was dominant in Molt-4 cells after 72-h treatment with Phx. The population of the early stage apoptotic cells and the late stage apoptotic/necrotic cells was almost equal in P3HR-1 cells in the presence of Phx, though the population of both types of cells increased with time. The nuclear morphological analysis of Phx-treated Raji, P3HR-1, and Molt-4 cells also showed that Phx induces apoptosis.
The present results suggest that Phx shows antitumor activity against human B cell-derived and T cell-derived lymphoblastoid cell lines, in vitro, causing apoptosis and necrosis.
Journal of Cancer Research and Clinical Oncology 08/2002; 128(7):363-8. · 2.56 Impact Factor
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ABSTRACT: Elderly patients with cerebrovascular disease have a high frequency of pneumonia due to impaired immune function and the occurrence of micro-aspiration.
We performed bronchoalveolar lavage in 11 very elderly subjects with cerebrovascular disease and 9 healthy volunteers to investigate whether there were changes of local immunity in the lungs of the elderly subjects. The total cell count, the cell characteristics, and the lymphocyte subsets in bronchoalveolar lavage fluid were compared between the two groups.
A significant increase in the total cell count as well as in the number of neutrophils and CD8(+) T cells was observed in the elderly group. In addition, the mean CD4/CD8 lymphocyte ratio was lower in the elderly patients than in the healthy volunteers.
These observations suggest that silent micro-aspiration occurs in many elderly individuals with cerebrovascular disease and that pulmonary defenses decrease with age.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 01/2002; 56(12):M771-4. · 4.60 Impact Factor
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ABSTRACT: The aim of this SPECT study was to investigate the effects of donepezil on regional cerebral blood flow (rCBF) in patients with mild to moderate Alzheimer's disease (AD) using statistical parametric mapping.
rCBF was noninvasively measured using (99m)Tc-ethyl cysteinate dimer in 35 AD patients with a Mini-Mental State Examination score > 16 on initial evaluation. Baseline and follow-up SPECT studies with a mean interval of 12 mo were performed on these patients. We used the adjusted rCBF images in the relative flow distribution (normalization of global cerebral blood flow for each patient to 50 mL/100 g/min with proportional scaling) to compare these groups through statistical parametric mapping.
In the follow-up study, the adjusted rCBF was significantly preserved in the right and left anterior cingulate gyri, right middle temporal gyrus, right inferior parietal lobules, and prefrontal cortex of donepezil-treated AD patients, compared with placebo-treated AD patients.
Treatment with donepezil for 1 y appears to reduce the decline in rCBF, suggesting preservation of functional brain activity.
Journal of Nuclear Medicine 11/2001; 42(10):1441-5. · 6.38 Impact Factor
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ABSTRACT: We compared the diagnostic usefulness of three-dimensional stereotactic surface projection (3D-SSP) with that of standard transaxial images in brain SPECT in patients with Alzheimer's disease (AD). The subjects consisted of 69 patients with AD and 60 patients with non-AD, including vascular dementia, Parkinson's disease with dementia, frontotemporal dementia, other dementing diseases and neuropsychiatric diseases. Standard transaxial section and 3D-SSP SPECT images with N-isopropyl-p-[123I] iodoamphetamine were blindly interpreted by three examiners and were classified into the following three patterns: typical AD, atypical AD, and not indicative AD patterns. The 3D-SSP images demonstrated reductions of cerebral blood flow in the parieto-temporal association cortex and posterior cingulate gyrus more clearly and easily than the standard transaxial images. The diagnostic sensitivity and specificity were 93% and 85% with 3D-SSP and 83% and 82% with standard transaxial section respectively. 3D-SSP was especially useful for early or atypical AD which showed no characteristic perfusion abnormalities on standard transaxial images. These results suggest that SPECT with 3D-SSP provides an sensitive as well as accurate tool for the diagnosis of AD.
Rinsho shinkeigaku = Clinical neurology 10/2001; 41(9):582-7.
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ABSTRACT: To estimate the usefulness of the bedside swallowing assessment proposed by Smithard et al and neuroimaging findings characteristic for dysphagia, we studied the outcome of 102 patients with chronic cerebral infarction after assessment of swallowing by this test with brain computerized tomography (CT). All patients had a variety of motor disturbance and were admitted on a long-term medicare basis. They were divided into two groups according to the findings: the positive group (n = 33), who showed any of the listed types of difficulty in swallowing water, and the negative group (n = 69). Followed up to 2.2 years, their outcomes were studied. CT findings were studied on type of infarction, number and laterality of infarction, grade of periventricular lucency (PVL), presence of ventricular dilatation (VD), and severity of cortical atrophy (CA). The mean age was 76.4 years at registration and 61 were men. The frequency of severe dementia and disturbed ADL were significantly higher in the positive group. Eighteen patients died during the observation period and 15 of those were in the positive group, indicating higher annual death rate (29.9% vs 2.2% in the negative group). All of the 15 patients in the positive group died of pneumonia. CT findings showed high incidence of multiple infarction, bilateral hemispheric lesion, severe PVL, VD, and severe CA in the positive group. These findings indicated that this evaluation method was useful in screening swallow function for patients with cerebral infarction in the chronic phase. Furthermore, CT findings suggested that severe white matter lesion, VD, and severe CA as well as multiple infarction seen in bilateral hemisphere was related to dysphagia, probably due to multiple factors involving pyramidal- and extrapyramidal-tracts with higher brain function.
Nippon Ronen Igakkai Zasshi Japanese Journal of Geriatrics 10/2001; 38(5):651-8.
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ABSTRACT: An 88-year-old woman was first referred to an eye clinic in mid-May 2000 because of limitation of ocular movement. A right orbital tumor was recognized on orbital CT scans and she was referred to our hospital. A chest X-ray film showed an abnormal mass in the right middle lung field, so she was admitted for further investigations. Adenocarcinoma was diagnosed by transbronchial lung biopsy. The right orbital tumor was thought to be a metastasis from the lung cancer. She received radiation therapy for the metastatic orbital tumor. However, two months after the onset of symptoms, she died due to progressive systemic metastasis. In summary, we report an elderly lung cancer patient whose initial symptoms were related to orbital metastasis.
Nippon Ronen Igakkai Zasshi Japanese Journal of Geriatrics 08/2001; 38(4):560-3.
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ABSTRACT: To clarify the present status and problems in medical care for the elderly with dementia, 103 cases were studied according to the descriptive records obtained at a public counselling facility for dementia, based on interviews with patients' families. Their records were analysed based on their background, severity of dementia (clinical dementia rating: CDR), and counselling content. There were 75 demented patients with a CDR score of 1 or more, and 50 of them were women aged 54 to 90, while the remaining 25 men were aged 55 to 88. The consultation content was clustered into 5 codes: code 1, evaluation of dementia and/or dementia-related symptoms including psychiatric symptoms and behavioral disturbance; code 2, methods to manage patients; code 3, methods to take a patient to a medical institution; code 4, questions regarding medical treatment and drugs prescribed at present; code 5, information on the welfare resources provided. In most of the 75 patients, the degree of dementia deteriorated insidiously without any physical symptoms. The key person and/or caregiver was usually an elderly spouse, and the family noticed dementia only after cognitive impairment progressed with or without troublesome symptoms. Hallucination was a common troublesome symptom. Concerning consultation content, codes 1, 2, and 3 were common, while 13 cases had dissatisfaction with their medical treatment. Therefore, it was necessary to explain the significance of early diagnosis of dementia to families and their caregivers. There were also many families who felt strain and wondered about what hospital or department to take the patient to. In addition, it seemed that explanation on the clinical course and adverse drug reactions, advice for the correspondence with psychiatric symptoms and abnormal behaviour, and information services concerning utilization of social resources was not yet sufficient.
Nippon Ronen Igakkai Zasshi Japanese Journal of Geriatrics 08/2001; 38(4):528-33.
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ABSTRACT: We measured the magnetisation transfer ratio (MTR) in the subcortical grey and white matter of 11 patients with idiopathic Parkinson's disease (PD) without dementia, six with PD with dementia (PDD), six with progressive supranuclear palsy (PSP), and 12 elderly control subjects to assess regional differences in structural brain damage. There were no significant differences in MTR in any region between PD and controls. However, patients with PDD had significantly lower MTR in the subcortical white matter, including the frontal white matter and the genu of the corpus callosum than the controls, whereas PSP had significantly lower MTR in the subcortical grey matter, including the putamen, globus pallidus and thalamus, in addition to the subcortical white matter. This suggests that regional patterns of structural brain damage can be detected using the magnetisation transfer technique. Measurement of MTR in the subcortical grey and white matter may be useful in differential diagnosis.
Neuroradiology 08/2001; 43(7):542-6. · 2.82 Impact Factor
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ABSTRACT: We measured magnetization transfer ratios (MTRs) of the hippocampus in 38 patients with Alzheimer's disease (AD), including very mild (Clinical Dementia Rating [CDR] 0.5, n=12), mild (CDR 1, n=14), and moderate stages (CDR 2, n=12), and in 21 healthy elderly control subjects. Medial temporal lobe atrophy was graded subjectively on a five-point scale by two observers blinded to clinical data. Compared with the controls, each of the AD groups, including the very mild group, had significant atrophy of the medial temporal lobe and a decrease in MTRs of the hippocampus. Logistic regression analysis revealed that the overall discrimination rate with MTR measurement and visual analysis of the atrophy was 85% and 73% between the control group and the CDR 0.5 group, 89% and 80% between the control group and the CDR 1 group, and 100% and 91% between the control group and the CDR 2 group, respectively. MTR measurements may provide additional information in detecting structural damage of the hippocampus of AD and be helpful in providing improved diagnosis and early detection of AD.
Journal of the Neurological Sciences 08/2001; 188(1-2):79-84. · 2.35 Impact Factor
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ABSTRACT: A 79-year-old woman was admitted on January 18, 2000, with a lumbar compression fracture. Two days after admission, a chest X-ray film showed reticular infiltrates in the right lung field. She was diagnosed as having pneumonia and was treated with antibiotics. Despite this therapy, her symptoms did not improve and the infiltrates diffusely extended to involve both lungs on chest X-ray films. She was placed on noninvasive positive pressure ventilation (NIPPV) for progressive respiratory failure at 5 days after admission in order to avoid endotracheal intubation. Her hypoxemia was immediately improved by oronasal bilevel positive airway pressure ventilation (BiPAP) and chest X-ray films revealed improvement of the reticular infiltrates. Measurement of viral antibody titers showed that the cause of acute respiratory failure was influenza A virus pneumonia. In conclusion, NIPPV may reduce the need for intubation of elderly patients with acute respiratory failure, as well as chronic obstructive pulmonary disease (COPD) patients.
Nippon Ronen Igakkai Zasshi Japanese Journal of Geriatrics 06/2001; 38(3):409-13.
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ABSTRACT: To evaluate the effect of ethyl icosapentaenoate (EPA) on the metabolism of tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta), the concentrations of these cytokines in the carotids of rabbits sheathed in a cuff were studied. Japanese white rabbits were divided into two groups; the EPA group, in which 600 mg/kg/day EPA was administered forcibly p.o. for 1 week before cuff treatment, and the control group. Carotid artery samples were obtained just before, 3 days and 7 days after cuff treatment, and TNFalpha and IL-1beta were determined separately with the Western blot analysis method. In the control group, there were 43.5 (+/- 3.0) pg/microg protein of TNFalpha and 53.5 (+/- 4.8) pg/microg protein of IL-1beta just before cuff treatment. Compared to the control group, these concentrations of the EPA group were both significantly low. Three days after cuff treatment, TNFalpha of the EPA group was still significantly low, while IL-1beta showed no difference. There was no significant difference between the two groups 7 days after cuff treatment. These findings suggested that EPA could influence TNFalpha and IL-1beta metabolism in the arterial wall even at baseline. Furthermore, EPA suppressed TNFalpha and IL-1beta production in the early phase of intimal thickening, indicating a mechanism inhibiting the activation of smooth muscle cells such as their proliferation and migration, induced by the cuff-sheath method.
Journal of atherosclerosis and thrombosis 02/2001; 8(2):45-9. · 2.69 Impact Factor
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Nippon Ronen Igakkai Zasshi Japanese Journal of Geriatrics 01/2001; 37(12):1012-3.
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ABSTRACT: When human erythrocytes were incubated with o-aminophenol at pH 7.0 at 37 degrees C for 46 hours, intracellular oxyhemoglobin was completely oxidized to methemoglobin during the initial 6 hours, and methemoglobin formed was then reduced to oxyhemoglobin during the following 20 hours. This was demonstrated by the changes in absorption spectra of intracellular hemoglobin. Such oscillatory behavior of intracellular hemoglobin during reaction with o-aminophenol was explained by the fact that o-aminophenol has the ability to both oxidize oxyhemoglobin and reduce methemoglobin. In order to study the mechanism of oxido-reductive reactions of hemoglobin with aromatic reductants including o-aminophenol, the oxidation of ferrous hemoglobin and reduction of methemoglobin with various aromatic reductants such as o-aminophenol, 2-amino-4-methyl-phenol, 2-amino-5-methylphenol, and homogentisic acid were investigated under various conditions. It was found that oxyhemoglobin was oxidized by these aromatic compounds, and the oxidation rate was accelerated in the presence of inositol hexaphosphate, but was not affected in the presence of catalase and superoxide dismutase, except for the case with homogentisic acid. The oxidation of ferrous hemoglobin by these compounds did not proceed under anaerobic conditions. Methemoglobin was reduced by these aromatic compounds, and the reduction rate was much accelerated in the presence of inositol hexaphosphate, but was not affected in the presence of catalase and superoxide dismutase, except for the case with homogentisic acid. The reduction of methemoglobin by these compounds proceeded under anaerobic conditions, suggesting that ferric heme of hemoglobin reacts directly with aromatic reductants. On the basis of these results, the mechanism of oxido-reductive reaction of ferrous and ferric hemoglobin with aromatic reductants was proposed.
The Tohoku Journal of Experimental Medicine 01/2001; 192(4):301-12. · 1.24 Impact Factor
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ABSTRACT: We investigated the relation between hippocampal damage and cerebral cortical dysfunction in Alzheimer's disease (AD) using MRI and SPECT. Nineteen patients with AD and 10 control subjects were studied. Hippocampal damage (including hippocampal formation, entorhinal cortex, and parahippocampal white matter) was assessed to evaluate the severity of atrophy and the magnetization transfer ratio (MTR) and cerebral cortical dysfunction was evaluated by quantitative cerebral blood flow (CBF) measurements using SPECT with 99mTc-ECD. Compared with controls, patients with AD had significantly more atrophy of the medial temporal lobe and a decrease in MTRs of the hippocampus and parahippocampus. There were significant correlations between the severity of hippocampal damage and regional CBF in temporoparietal lobes. Mini-Mental State Examination scores significantly correlated with the severity of hippocampal damage and regional CBFs in temporoparietal lobes. These results suggest that the functional effect of hippocampal damage occurs in temporoparietal lobes in AD, probably due to neuronal disconnections between hippocampal areas (including the entorhinal cortex) and temporoparietal lobes.
Nippon Ronen Igakkai Zasshi Japanese Journal of Geriatrics 12/2000; 37(11):921-7.
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ABSTRACT: Homogentisic acid (HGA) causes oxidation of human oxyhemoglobin and reduction of methemoglobin. The rate of oxidation of oxyhemoglobin by HGA is greatly accelerated in the presence of myo-inositol hexakis-phosphate (P6-inositol) or superoxide dismutase (SOD), but is inhibited in the presence of catalase. The reduction rate of methemoglobin by HGA is accelerated in the presence of P6-inositol but is greatly inhibited in the presence of SOD. It is suggested that the semiquinone and quinone form of HGA and oxygen radicals may be involved in the mechanism of oxido-reductive reactions of human hemoglobin with HGA. In addition, a new anodic hemoglobin found by isoelectric focusing electrophoresis was produced during the reaction of oxyhemoglobin with HGA. When human erythrocytes were exposed to HGA for several hours at 37 degrees C (pH 7.4), the anodic oxyhemoglobin (HGA-modified hemoglobin) and its half met-form hemoglobin [(alpha3+beta2+)2 of HGA-modified hemoglobin] were produced in significant amounts. HGA-modified hemoglobin was stably purified and showed increased oxygen affinity, absence of titratable sulfhydryl groups, and the absorption spectrum of normal oxyhemoglobin. Our results demonstrate that HGA shows multiple effects on human hemoglobin and erythrocytic hemoglobin, which is consistent with the evidence that HGA is involved in various pathological conditions such as arthritis and carcinogenesis in humans.
International Journal of Hematology 11/2000; 72(3):318-24. · 1.27 Impact Factor
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ABSTRACT: This study was conducted to evaluate the relationship between arteriosclerosis and lipoprotein(a) [Lp(a)] from the point of view of aging. A total of 354 patients (167 men) aged 60 or more were enrolled and serum Lp(a) levels, vascular risks, and complications were studied. Patients were divided into 3 groups according to age: group I (n = 73: aged 60 to 69), group II (n = 144: aged 70-79), and group III (n = 137: aged 80 or more). Vascular complications were assessed by carotid ultrasonography (US), ECG, and ankle pressure index (API), US findings were stratified according to the distribution of plaque lesions in unilateral and bilateral lesions, while plaque types were subdivided based on the morphology and US echogenicity. Male patients with risk factors (diabetes, hypercholesterolemia, cigarette smoking) as well as stroke were frequent in group I, indicating some selection bias. However, there was no difference in Lp(a) level among the three groups. Carotid lesions, especially bilateral lesions with more thickened plaques, and low API were both significantly frequent in group III. Logistic regression analysis showed that carotid lesions were influenced not only by aging, but also independently by high Lp(a) levels in group III, and by hypertension in group II. A high Lp(a) level was related to hypercholesterolemia and hypoechoic plaque. These findings indicated that atherosclerosis, which developed in both the carotid and peripheral arteries with aging, was related to different risks in each decade of life. Furthermore, it seems that a long period of high Lp(a) levels may promote the formation of hypoechoic plaque.
Nippon Ronen Igakkai Zasshi Japanese Journal of Geriatrics 11/2000; 37(10):811-8.
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Nippon Ronen Igakkai Zasshi Japanese Journal of Geriatrics 09/2000; 37(8):611-2.
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ABSTRACT: Although atrophy of structures in the medial temporal lobe has been considered an indication of Alzheimer's disease (AD), atrophic changes on MR images have also been associated with other dementing diseases and are not specific to AD. This study was undertaken to determine whether characteristic alterations in the hippocampus of patients with AD are detectable with magnetization transfer (MT) imaging.
Coronal MT imaging was performed in 35 patients with probable AD, in 14 patients with vascular dementia, in 13 patients with other types of dementia, and in 23 control subjects to measure MT ratios of the hippocampus. Medial temporal lobe atrophy was graded subjectively on a five-point scale.
Scores of medial temporal lobe atrophy in all dementia groups were significantly higher than those in control subjects, but no differences were found among the dementia groups. MT ratios in the hippocampus were significantly lower in patients with AD than in those with non-AD dementia and in the control subjects; however, no differences were found between the non-AD dementia patients and the control subjects. MT ratio measurements were better than visual analysis of atrophy for differentiating AD patients from those with non-AD dementia (an overall discrimination rate of 77% versus 65%). MT ratios significantly correlated with scores on the Mini-Mental State Examination and with medial temporal lobe atrophy in AD patients but not in patients with non-AD dementia.
MT measurements may be more specific than visual analysis in detecting structural damage of the hippocampus in AD patients and might be useful in discriminating AD from vascular dementia and other types of dementia.
American Journal of Neuroradiology 09/2000; 21(7):1235-42. · 2.93 Impact Factor
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ABSTRACT: To clarify the factors influencing platelet function in elderly patients with chronic thrombotic disease, platelet aggregability was studied in 839 blood samples from 497 patients with a variety of diseases. Clinical stage (thrombotic disease), vascular risk factors, and data concerning any administration of antiplatelet drugs were assessed, as well as brain computerized tomographic and carotid ultrasonographic findings. Platelet aggregability was determined spectrophotometrically with an aggregometer (PAM-8T) and adenosine-5'-diphosphate as an agonist to determine new parameters: the grading curve (GC) type, and platelet aggregability threshold index (PATI). Multiple regression analysis showed that the antiplatelet therapy greatly influenced the GC type. Platelet aggregability, which accelerated with aging, was strongly suppressed by ticlopidine. Furthermore, excluding samples with antiplatelet therapy, statistical analysis showed that platelet aggregability was accelerated in women, and in patients with bilateral or complicated carotid lesions, although these patients were significantly older than the others. These findings suggested that accelerated aggregability in the elderly substantially reflected the progress of arteriosclerosis with age. Moreover, the findings indicated that the determination of GC type and PATI were useful in monitoring elderly patients receiving antiplatelet therapy, especially with ticlopidine.
Nippon Ronen Igakkai Zasshi Japanese Journal of Geriatrics 09/2000; 37(8):619-26.
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ABSTRACT: The aim of this SPECT study was to determine the initial abnormality and longitudinal changes in regional cerebral blood flow (rCBF) in early Alzheimer's disease (AD) using statistical parametric mapping (SPM).
rCBF was noninvasively measured using (99m)Tc-ethyl cysteinate dimer SPECT in 32 patients complaining of mild cognitive impairment, with a Mini-Mental State Examination score more than 24 at the initial study, and 45 age-matched healthy volunteers. All patients satisfied the diagnostic criteria of AD during the follow-up period of at least 2 y. Follow-up SPECT studies were performed on the patients at a mean interval of 15 mo. We used the raw data (absolute rCBF parametric maps) and the adjusted rCBF images of relative flow distribution (normalization of global cerebral blood flow [CBF] for each subject to 50 mL/100 g/min with proportional scaling) to compare these groups with SPM.
In the baseline study, the adjusted rCBF was significantly and bilaterally decreased in the posterior cingulate gyri and precunei of patients compared with healthy volunteers. In the follow-up study, selected reduction of the adjusted rCBF was observed in the left hippocampus and parahippocampal gyrus. These areas showed the most prominent reduction in absolute rCBF on each occasion. Moreover, further decline of the absolute rCBF was longitudinally observed in extensive areas of the cerebral association cortex.
SPM analysis showed the characteristic early-AD rCBF pattern of selective decrease and longitudinal decline, which may be overlooked by a conventional region-of-interest technique with observer a priori choice and hypothesis. This alteration in rCBF may closely relate to the pathophysiologic process of this disease.
Journal of Nuclear Medicine 08/2000; 41(7):1155-62. · 6.38 Impact Factor
