Seiju Kobayashi

Quantitative analysis of brain perfusion SPECT in Alzheimer's disease using a fully automated regional cerebral blood flow quantification software, 3DSRT

PURPOSE The clinical symptoms of Alzheimers disease (AD) show great diversity depending on the clinical stage. We investigated the correlation of regional cerebral blood flow (rCBF) changes and the clinical severity of AD patients. METHODS Thirty-nine AD patients and 16 normal subjects participated in this study. AD patients were divided into three subgroups by clinical severity. Quantitative brain perfusion SPECT analyses were performed using a rCBF quantification software, 3DSRT. RESULTS In mild AD, significant decreases of rCBF were detected in the bilateral parietal, angular gyrus, pericallosal, thalamus, right temporal and left hippocampal regions. Moderate AD patients showed significantly lower blood flow than those with mild AD only to the right hippocampus. Analysis of the severe AD group revealed a nearly diffuse decrease of rCBF throughout the cerebral cortex except for part of the frontal lobe compared with moderate patients. CONCLUSIONS These results were consistent with previous findings demonstrated by qualitative analysis of CBF. The decreased thalamic blood flow was noteworthy as this finding has rarely been reported. In consideration of the structure and function of the Papez circuit, which connects the medial temporal lobe and thalamus, a remote metabolic effect might be the cause of lower rCBF in the thalamus.

Decreased cardiac MIBG uptake, its correlation with clinical symptoms in dementia with Lewy bodies

Recent studies have demonstrated the usefulness of 123I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy for the diagnosis of dementia with Lewy bodies (DLB). In this study, we investigated the relationship between decreased cardiac MIBG uptake and clinical symptoms in DLB. Thirty-six patients with probable DLB and six normal controls underwent MIBG scintigraphy. We measured the early and delayed heart-to-mediastinum (H/M) ratios, and the results between subgroups based on the presence and absence of clinical symptoms were compared. The mean early and delayed H/M ratios were 1.55+/-0.29 and 1.42+/-0.30, and 30 (83.3%) and 33 (91.7%) subjects showed lower values compared to the cutoff, respectively. A statistically significant difference was found only between groups with and without orthostatic hypotension (OH). Among 10 DLB subjects without Parkinsonism, nine patients had a decreased H/M ratio in the delayed image. To our knowledge, this is the first study to correlate decreased MIBG uptake with the clinical symptoms of DLB, and to show a significantly lower H/M ratio in subjects with OH. Furthermore, we found that MIBG scintigraphy could detect cardiac sympathetic denervation regardless of clinically evident Parkinsonism. These results suggest that MIBG myocardial scintigraphy could be a valuable diagnostic test in the clinical diagnosis of DLB.

Imaging Improves Diagnosis of Dementia with Lewy Bodies

Dementia with Lewy bodies (DLB) is the second most common cause of degenerative dementia after Alzheimers disease (AD), and is clinically characterized by the progressive cognitive decline with fluctuations in cognition and alertness, recurrent visual hallucinations and Parkinsonism. Once these characteristic symptoms of DLB emerge, discriminating it from AD is relatively easy. However, in the early disease stages, the clinical symptoms of various types of dementias largely overlap and it is difficult to distinguish DLB from other neurodegenerative dementias based on clinical manifestations alone. To increase the accuracy of antemortem diagnosis of DLB, the latest diagnostic criteria incorporate findings from 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy, or from neuroimaging such as computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET). In the present guidelines, decreased dopamine transporter uptake revealed by SPECT or PET receives the greatest importance among various neuroimaging findings and is listed as one of the suggestive features. Supportive features that commonly present but are not proven to have diagnostic specificity include relatively-preserved medial-temporal-lobe structures, occipital hypoperfusion, and abnormal MIBG myocardial scintigraphy. In this paper, we review the major findings on various neuroimaging modalities and discuss the clinical usefulness of them for the diagnosis of DLB. Although there is not enough evidence to reach the conclusion, considering the accessibility in clinical practice, in our personal views, we recommend the use of brain-perfusion SPECT and MIBG myocardial scintigraphy to improve the diagnosis of DLB.

Comparison of the Usefulness of Brain Perfusion SPECT and MIBG Myocardial Scintigraphy for the Diagnosis of Dementia with Lewy Bodies

Background: Supportive features in the diagnostic criteria for dementia with Lewy bodies (DLB) include occipital hypoperfusion and decreased cardiac uptake of 123I-metaiodobenzylguanidine (MIBG). In this study, we performed both brain perfusion single photon emission computed tomography (SPECT) and MIBG myocardial scintigraphy in the same subjects and evaluated their sensitivity to detect the characteristic features of DLB. Methods: Twenty-five patients with probable DLB (76.8 ± 5.1 years old, 10 male) underwent 99mTc-ethylcysteinate dimer brain perfusion SPECT and 123I-MIBG myocardial scintigraphy. The results of SPECT were analyzed using a qualitative analysis program, easy Z score imaging system (eZIS), and an automated quantitative analysis program, 3DSRT. Results: Qualitative analysis using eZIS demonstrated occipital hypoperfusion in 17 subjects (68%). The quantified mean blood perfusion in the occipital segment on the 3DSRT template was 40.7 ± 5.03 ml/100 g/min (right) and 40.5 ± 5.38 ml/100 g/min (left), and in 19 DLB patients these values were below the normal limit. Twenty-four of 25 subjects (96%) had decreased cardiac MIBG uptake in the delayed image. Conclusion: MIBG myocardial scintigraphy was superior to brain perfusion SPECT in detecting a characteristic feature of DLB. Our results suggest that combining SPECT and MIBG scintigraphy could increase the accuracy of clinical diagnosis of DLB.

Apolipoprotein E4 frequencies in a Japanese population with Alzheimer's disease and dementia with Lewy bodies.

Background The apolipoprotein E (APOE) ε4 allele has been reported to be a risk factor for Alzheimers disease (AD) and dementia with Lewy bodies (DLB). Previous neuropathological studies have demonstrated similar frequencies of the APOE ε4 allele in AD and DLB. However, the few ante-mortem studies on APOE allele frequencies in DLB have shown lower frequencies than post-mortem studies. One reason for this may be inaccuracy of diagnosis. We examined APOE genotypes in subjects with AD, DLB, and a control group using the latest diagnostic criteria and MRI, SPECT, and MIBG myocardial scintigraphy. Methods The subjects of this study consisted of 145 patients with probable AD, 50 subjects with probable DLB, and a control group. AD subjects were divided into two groups based on age of onset: early onset AD (EOAD) and late onset AD (LOAD). All subjects had characteristic features on MRI, SPECT, and/or myocardial scintigraphy. Results The rate of APOE4 carrier status was 18.3% and the frequency of the ε4 allele was 9.7% in controls. The rate of APOE4 carrier status and the frequency of the ε4 allele were 47% and 27% for LOAD, 50% and 31% for EOAD, and 42% and 31% for DLB, respectively. Conclusion The APOE4 genotypes in this study are consistent with previous neuropathological studies suggesting accurate diagnosis of AD and DLB. APOE4 genotypes were similar in AD and DLB, giving further evidence that the ε4 allele is a risk factor for both disorders.

Two-Layer Appearance on Brain Perfusion SPECT in Idiopathic Normal Pressure Hydrocephalus: A Qualitative Analysis by Using Easy Z-Score Imaging System, eZIS

Background/Aims: It is often difficult to distinguish idiopathic normal pressure hydrocephalus (iNPH) from other neurodegenerative disorders such as Alzheimer’s disease (AD). To understand the characteristic pattern of blood flow in iNPH, we performed brain perfusion SPECT and analyzed the results by using the easy Z-score imaging system (eZIS). Methods: Subjects were 12 patients with probable iNPH and 10 probable AD patients with prominent ventriculomegaly. They underwent brain perfusion SPECT using 99mTc-ethylcysteinate dimer as a tracer. Results: The two-tailed view display in eZIS demonstrated an obvious two-layer structure consisting of decreased blood flow around the corpus callosum and, in iNPH, enhanced perfusion in areas surrounding the cingulate gyrus in the sagittal view, while no AD cases showed these findings. Conclusion: Hypoperfusion around the corpus callosum in iNPH could be, at least partially, a false-positive finding due to an insufficient anatomical standardization of SPECT images caused by an abnormally enlarged ventricle. Increased blood perfusion in the external layer adjacent to the hypoperfused area might be caused by increased radioisotope count per volume resulting from exclusion of cerebral cortex by a dilated ventricle. Our results demonstrate that a two-layer appearance revealed by the two-tailed view analysis of brain perfusion SPECT using eZIS could be a means to detect iNPH.

Decreased blood perfusion in right thalamus after transient global amnesia demonstrated by an automated program, 3DSRT

TRANSIENT GLOBAL AMNESIA (TGA) is a sudden-onset, temporary loss of memory function characterized by anterograde amnesia. Because the episode usually lasts only 6–8 h, it is difficult to perform detailed analysis of cerebral blood flow (CBF) during TGA. We report a TGA patient who had unique hemodynamics after the attack. Written informed consent was obtained. A 58-year-old right handed man with unremarkable medical history came to the emergency room complaining of difficulty in retaining new information at 2:30 a.m. The amnestic episode abruptly started at around 10:00 p.m. the previous day soon after he took a bath. Physical work-up indicated no abnormalities. On Mini-Mental State Examination (MMSE) he lost 3 points for not recalling three words. At 10:30 a.m. he was examined on technetium-99m ethyl cysteinate dimer brain perfusion single-photon emission computed tomography (Tc-ECD-SPECT) followed by magnetic resonance imaging/angiography (MRI/MRA) and diffusionweighted imaging (DWI), which ruled out any cerebrovascular events. The episode of TGA resolved suddenly at 1:00 p.m., that is, his amnestic episode continued for 15 h. He achieved full marks on the MMSE soon after the termination of TGA. Follow-up evaluation was performed 4 weeks later. The results of ECD-SPECT during and after TGA were investigated using an automated blood-flow-analysis program 3DSRT. 3DSRT indicated a relatively diffuse and unilateral decrease of CBF in the right hemisphere during the acute phase. However, regional CBF of the bilateral hippocampi, in which most previous reports demonstrated significant changes during TGA attacks, was preserved as was that of the thalamus as well. The most notable finding was significantly decreased CBF of the right thalamus at follow up despite no visible regions on MRI/MRA and DWI. The quantified CBF values in thalamus were as follows (right/left): during attack, 44.2/ 44.1 mL/100 g per min; follow up, 37.4/45.5 mL/ 100 g per min; lower limits of normal database, 43.9/42.7 mL/100 g per min. The true pathophysiology of TGA remains unclear. Among several possible causes proposed so far, an ischemic event is the most feasible mechanism at the moment. In the present case DWI during and after the episode indicated no abnormalities. Quinette et al. reviewed previous publications and demonstrated that 42 of 43 patients who were examined on SPECT during the acute phase had transient dysfunction in the medial temporal lobe. The analysis of ECD-SPECT in the present case using 3DSRT indicated atypical findings of significantly decreased CBF of the right thalamus after the TGA attack in spite of preserved blood flow during the acute phase. At the present time we cannot clearly explain the mechanisms of these findings. It is possible that we captured a moment of some sort of reversible vascular event, therefore it is necessary to accumulate more cases.

The usefulness of combined brain perfusion single‐photon emission computed tomography, Dopamine‐transporter single‐photon emission computed tomography, and 123I‐metaiodobenzylguanidine myocardial scintigraphy for the diagnosis of dementia with Lewy bodies

Current diagnostic criteria recommend neuroimaging as a diagnostic support tool for the clinical diagnosis of dementia with Lewy bodies (DLB). Because DLB causes characteristic impairments and disabilities, such as neuroleptic hypersensitivity, which may significantly increase morbidity and mortality, its prompt and correct diagnosis is very important. The aim of this study was to evaluate the extent to which diagnostic accuracy can be increased by using different combinations of brain perfusion single‐photon emission computed tomography (bp‐SPECT), 123 I‐metaiodobenzylguanidine myocardial scintigraphy (MIBG scintigraphy), and DAT‐SPECT. Taking finances and patient burden into consideration, we compared the tests to determine priority.

The usefulness of combined brain perfusion SPECT, DAT-SPECT and MIBG scintigraphy for the diagnosis of dementia with Lewy bodies

Background & Aim: Current diagnostic criteria recommend neuroimaging as a diagnostic support tool for the clinical diagnosis of dementia with Lewy bodies (DLB). Because DLB causes characteristic impairments and disabilities, such as neuroleptic hypersensitivity, which may significantly increase morbidity and mortality, its prompt and correct diagnosis is very important. The aim of this study was to evaluate the extent with which diagnostic accuracy can be increased using a combination of brain perfusion SPECT (bp-SPECT), I-metaiodobenzylguanidine Myocardial Scintigraphy (MIBG scintigraphy) and DAT-SPECT. Taking finances and patient burden into consideration, we compared the tests to determine priority.Background: Patients with acute ischemic stroke are at a higher risk of developing cognitive impairment. Cognitive impairment is often associated with cytokine activation. Aim: To assess the pattern of cognitive impairment in patients with acute ischemic stroke and to explore its relationship to the inflammatory markers. Patients & Methods: 44 patients with acute ischemic stroke (1st 48 hours) were subjected to neurological examination, assessment of stroke disability using National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS), neuropsychological assessment using mini mental state examination (MMSE), Montreal cognitive assessment (MoCA) scale, trail making test-B (TMT-B) and controlled oral word association test (COWAT), measurement of (IL-8, ESR, CRP) levels and neuroimaging. 44 ages, sex and educational level matched controls were included for comparison of neuropsychological tests and serum level of IL-8. Results: The patients showed worse performance in neuropsychological tests (MMSE, MoCA, COWAT, TMT-B) than controls. The level of IL-8 was significantly higher in all patients than the control subjects. There was a significant negative correlation between the serum level of IL-8 and both screening (MoCA) and detailed (COWAT) cognitive assessment. Significant negative correlation was found between the IL-8 serum level and TMT-B. Conclusion: The cognitive impairment in early acute ischemic stroke is highly correlated to the serum level of IL-8.

PS198. Pathological analysis of refractory depression using fetal alcohol and adolescent corticosterone double stress model

Objectives: The purpose of this study is to investigate the alterations of the hypothalamic-pituitary-adrenal axis hormones, especially salivary cortisol and dehydroepiandrosterone (DHEA) in perinatal depression. Methods: 44 patients with depression and 217 normal subjects in perinatal period were included in this study. Edinburgh Postnatal Depression Scale(EPDS) and Beck Depression Inventory II(BDI-II) were performed. The subjects below 10 points of EPDS score or below 13 points of BDI-II score were classified to normal subjects. Among the subjects more than 11 points of EPDS score or more than 14 points of BDI-II score were diagnosed depression by DSM-IV TR by psychiatrists. All subjects were to collect their saliva in each 4 collecting tubes, immediately upon awakening(IA), 30 minutes after awakening(30A), 60 minutes after awakening(60A) and before bedtime(BB). Results: The number of subjects in antenatal period were 103, and antenatal depression(AD) patients were 21, antenatal normal(AN) subjects were 82. The number of subjects in postnatal period were 114, and postnatal depression(PD) patients were 23, postnatal normal(PN) subjects were 91. Salivary cortisol levels in subjects with AD collected IA, 30A and 60A were lower than with AN subjects significantly except BB. Salivary cortisol levels in subjects with PD collected 60A only were lower than with PN subjects significantly. Salivary DHEA levels in subjects with both AD and PD were lower than with normal subjects significantly. Also cortisol/DHEA ratio(F/D ratio) in subjects with both AD and PD were much higher than with normal subjects significantly. Conclusions: These results suggest that the blunted response was shown in AD, and the characteristics between AD and PD are different. Also the differences of salivary DHEA levels and F/D ratio between subjects with PD and normal subjects are suggested the one of the key points of difference among both groups. PS197 Low level of perineuronal nets in the medial prefrontal cortex predicts vulnerability to stress Na Chen,1 Die Hu,1 Lin Lu,1,2,3 Jie Shi 1 1National Institute on Drug Dependence, Peking University, Beijing, China; 2Institute of Mental Health/Peking University Sixth Hospital and Key Laboratory of Mental Health, Ministry of Health, Beijing, China; 3Peking-Tsinghua Center for Life Sciences and PKU-IDG/ McGovern Institute for Brain Research; Abstract Perineuronal nets (PNNs) are extracellular matrix structures enwrapping parvalbumin-positive γ-aminobutyric acid (GABA)ergic interneurons which are crucial for modulating anxiety and depressive-like behaviors. Perineuronal nets have recently been implicated in experience-dependent neuroplastic changes in central nervous system, but it is poorly understood that whether PNNs modulates the neural maladaptation after repeated exposure to stress. We found that adolescent rats with vulnerability to chronic unpredictable mild stress (CUMS) showed decreased level of PNNs, tenascin-R and aggrecan in the medial prefrontal cortex (mPFC). Degradation of PNNs in mPFC produced vulnerability to stress in adult rats. Elevating PNNs in the mPFC through environment enrichment prevented CUMS-induced depressive and anxiety-like behavior. Fluoxetine reversed the stress vulnerability in adolescent rats and increased PNNs levels. Lower level of PNNs rendered GABAergic neurons susceptible to CUMS, manifesting as decreases in expression of glutamic acid decarboxylase 67 (GAD 67) and frequency and amplitude of inhibitory postsynaptic current (IPSC) after CUMS. The organization of PNNs coincided with the developmental switch in stress vulnerability to resilience. These findings indicate a role of PNNs in mPFC in predicting and modulating vulnerability to stressinduced depressive-like behavior, and the effect may be produced though regulating GABAergic functions.