123I-MIBG myocardial scintigraphy for the diagnosis of DLB: a multicentre 3-year follow-up study.

BACKGROUND AND PURPOSE: We previously reported the usefulness of iodine-123 metaiodobenzylguanidine (123I-MIBG) myocardial scintigraphy for differentiation of dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) in a cross-sectional multicentre study. The aim of this study was, by using reassessed diagnosis after 3-year follow-up, to evaluate the diagnostic accuracy of 123I-MIBG scintigraphy in differentiation of probable DLB from probable AD. METHODS: We undertook 3-year follow-up of 133 patients with probable or possible DLB or probable AD who had undergone 123I-MIBG myocardial scintigraphy at baseline. An independent consensus panel made final diagnosis at 3-year follow-up. Based on the final diagnosis, we re-evaluated the diagnostic accuracy of 123I-MIBG scintigraphy performed at baseline. RESULTS: Sixty-five patients completed 3-year follow-up assessment. The final diagnoses were probable DLB (n=30), possible DLB (n=3) and probably AD (n=31), and depression (n=1). With a receiver operating characteristic curve analysis of heart-to-mediastinum (H/M) ratios for differentiating probable DLB from probable AD, the sensitivity/specificity were 0.77/0.94 for early images using 2.51 as the threshold of early H/M ratio, and 0.77/0.97 for delayed images using 2.20 as the threshold of delayed H/M ratio. Five of six patients who were diagnosed with possible DLB at baseline and with probable DLB at follow-up had low H/M ratio at baseline. CONCLUSIONS: Our follow-up study confirmed high correlation between abnormal cardiac sympathetic activity evaluated with 123I-MIBG myocardial scintigraphy at baseline and the clinical diagnosis of probable DLB at 3-year follow-up. Its diagnostic usefulness in early stage of DLB was suggested. TRIAL REGISTRATION NUMBER: UMIN00003419.

Improvement in delusions and hallucinations in patients with dementia with Lewy bodies upon administration of yokukansan, a traditional Japanese medicine.

BACKGROUND: This multicentre open-label trial examined the efficacy and safety of the traditional Japanese medicine, or Kampo medicine, yokukansan (YKS), for behavioural and psychological symptoms of dementia (BPSD) in patients with dementia with Lewy bodies. METHODS: Sixty-three dementia with Lewy bodies patients with probable BPSD (M:W, 30:33; mean age, 78.2±5.8 years) were enrolled and treated with YKS for 4 weeks. RESULTS: Significant improvements in Neuropsychiatric Inventory scores (mean decrease, 12.5 points; P<0.001) and Zarit Burden Interview-Japanese edition tests (mean decrease, 3.6 points; P=0.024) were observed. In patients who consented to an assessment after 2 weeks of treatment, a time-dependent significant improvement was observed in the Neuropsychiatric Inventory score (n=23; mean decrease, 14.4; P<0.001), each subscale, including delusions and hallucinations, the Zarit Burden Interview-Japanese edition (n=22; mean decrease, 8.2; P<0.01) and the behavioural pathology in Alzheimer's disease insomnia subscale. The Mini-Mental State Examination and the Disability Assessment for Dementia (DAD) showed no significant change. Adverse events were observed in 11 (18%) patients. Three patients (5%) discontinued YKS due to adverse reactions, namely, spasticity and exacerbation of BPSD, edema, and nausea. Hypokalaemia (<3.5 mEq/L) was present in four patients (6%) at the study endpoint. Worsening of extrapyramidal symptoms was not observed. CONCLUSION: YKS improved BPSD in dementia with Lewy bodies patients and caregiver burden scores without deterioration in cognitive function. YKS is useful for the treatment of delusions and hallucinations in BPSD.

The Japanese MCI screen for early detection of Alzheimer's disease and related disorders.

Early detection of Alzheimer's disease and related disorders in Japan is increasingly important. The Mild Cognitive Impairment Screen (MCIS)-derived from the National Institute of Aging CERAD neuropsychologic battery-differentiates normal aging from MCI and mild dementia with 97.3% and 99% accuracy, respectively. The Japanese MCIS (JMCIS), Mini-Mental State Examination (MMSE), quantitative SPECT (qSP), and quantitative MRI (qMRI) were used to classify 63 outpatients at Fukuoka University Hospital who were either normal or had MCI based on Clinical Dementia Rating scores of 0 and 0.5, respectively. Performance statistics for the JMCIS, MMSE, qSP, and qMRI were, respectively: (1) accuracy = 0.964, 0.768, 0.722, 0.733; (2) sensitivity = 0.958, 0.792, 0.688, 0.700; (3) specificity = 1.000, 0.625, 1.000, 1.000; and (4) kappa validity = 0.813, 0.420, 0.296, 0.308. This initial study shows negligible differences between the English and Japanese MCIS, supporting its potential use for early detection in Japan.

Diagnostic accuracy of 123I-meta-iodobenzylguanidine myocardial scintigraphy in dementia with Lewy bodies: a multicenter study.

BACKGROUND AND PURPOSE: Dementia with Lewy bodies (DLB) needs to be distinguished from Alzheimer's disease (AD) because of important differences in patient management and outcome. Severe cardiac sympathetic degeneration occurs in DLB, but not in AD, offering a potential system for a biological diagnostic marker. The primary aim of this study was to investigate the diagnostic accuracy, in the ante-mortem differentiation of probable DLB from probable AD, of cardiac imaging with the ligand 123I-meta-iodobenzylguanidine (MIBG) which binds to the noradrenaline reuptake site, in the first multicenter study. METHODS: We performed a multicenter study in which we used 123I-MIBG scans to assess 133 patients with clinical diagnoses of probable (n = 61) or possible (n = 26) DLB or probable AD (n = 46) established by a consensus panel. Three readers, unaware of the clinical diagnosis, classified the images as either normal or abnormal by visual inspection. The heart-to-mediastinum ratios of 123I-MIBG uptake were also calculated using an automated region-of-interest based system. RESULTS: Using the heart-to-mediastinum ratio calculated with the automated system, the sensitivity was 68.9% and the specificity was 89.1% to differentiate probable DLB from probable AD in both early and delayed images. By visual assessment, the sensitivity and specificity were 68.9% and 87.0%, respectively. In a subpopulation of patients with mild dementia (MMSE ≥ 22, n = 47), the sensitivity and specificity were 77.4% and 93.8%, respectively, with the delayed heart-to-mediastinum ratio. CONCLUSIONS: Our first multicenter study confirmed the high correlation between abnormal cardiac sympathetic activity evaluated with 123I-MIBG myocardial scintigraphy and a clinical diagnosis of probable DLB. The diagnostic accuracy is sufficiently high for this technique to be clinically useful in distinguishing DLB from AD, especially in patients with mild dementia.

Superiority of 3-dimensional stereotactic surface projection analysis over visual inspection in discrimination of patients with very early Alzheimer's disease from controls using brain perfusion SPECT.

UNLABELLED: In Alzheimer's disease (AD), regional cerebral blood flow (rCBF) in the posterior cingulate gyri and precunei has been reported to decrease even at a very early stage. It may be helpful to use statistical image analysis to distinguish slight decreases in rCBF in this area. We compared a 3-dimensional stereotactic surface projection (3D-SSP) technique with visual inspection in the discrimination of patients with very early AD from age-matched controls using brain perfusion SPECT. METHODS: SPECT was obtained in 38 patients with probable AD at a very early stage and after a mean interval of 15 mo and in 76 age-matched healthy volunteers. We randomly divided these subjects into 2 groups. The first group was used to identify the areas with significant decreases of rCBF in patients compared with healthy control subjects based on the voxel-based analysis using 3D-SSP. The second group was used to compare the discrimination ability between patients and control subjects by 3D-SSP with that by visual inspection. In the second group, a Z-score map for a SPECT image of a subject was obtained by comparison with mean and SD SPECT images of control subjects for each voxel after anatomic standardization and voxel normalization to reference regions. Receiver operating characteristic (ROC) curves for a Z-score discriminating patients with AD from control subjects were analyzed in areas with significant decreases of rCBF identified in the first group. For visual inspection, 6 physicians graded the rCBF decrease on SPECT images for ROC curves. They inspected the images twice at an interval of >2 wk, and intra- and interobserver reliabilities were determined. RESULTS: Visual inspection showed fair-to-excellent intra- and interobserver reliabilities. The 3D-SSP demonstrated an accuracy of 86.2% for discriminating patients with AD from control subjects when analyzing the posterior cingulate gyri and precunei with global mean normalization. In contrast, visual inspection did not show an accuracy of >74.0% for this discrimination. CONCLUSION: The ability of 3D-SSP to discriminate patients with very early AD from control subjects is superior to that of visual inspection. It is clinically useful and reliable to adopt the use of 3D-SSP as an adjunct to visual interpretation.

Longitudinal evaluation of both morphologic and functional changes in the same individuals with Alzheimer's disease.

UNLABELLED: Morphologic and functional imaging studies have not always given concordant results about brain areas showing atrophic changes and reduced flow or metabolism in Alzheimer's disease (AD). The aim of this study was to determine the initial abnormality and the longitudinal changes in both morphologic and functional measurements for the same individuals with AD. METHODS: We investigated 15 patients with mild AD and 25 age-matched healthy volunteers. The AD patients underwent both MRI and SPECT 3 times at intervals of approximately 1 y. The gray matter volume, as segmented from MRI, and the regional cerebral blood flow (rCBF), as measured by SPECT, of AD patients were compared with those of healthy volunteers using statistical parametric mapping, which is a voxel-based analysis in stereotactic space. RESULTS: Considerable discordance between areas of regional atrophy and areas of decreased rCBF was observed. The medial temporal areas showed a faster and more extensive reduction of gray matter volume than of rCBF. In comparison with the value at the baseline study, rCBF in the posterior cingulate gyrus and precuneus and the associative parietal cortex was extensively decreased. In contrast, the extent of significant decrease in this area continued to be much narrower for gray matter volume than for rCBF, even in the follow-up studies. Frontal areas, including the anterior cingulate gyrus and the orbitofrontal areas, showed a progressive reduction in both rCBF and gray matter volume. The reduction in rCBF was in a more posterior part of the associative temporal cortex than was the reduction in gray matter volume. CONCLUSION: These results indicate a distinct discordance between morphologic and functional changes in a longitudinal study of AD. Functional changes may be caused partly by remote effects from the morphologically involved areas with decreased connectivity and partly by a compensatory response by neuronal plasticity.

Correction for partial-volume effects on brain perfusion SPECT in healthy men.

UNLABELLED: The limited spatial resolution of SPECT scanners does not allow an exact measurement of the local radiotracer concentration in brain tissue because partial-volume effects (PVEs) underestimate concentration in small structures of the brain. The aim of this study was to determine which brain structures show greater influence of PVEs in SPECT studies on healthy volunteers and to investigate aging effects on SPECT after the PVE correction. METHODS: Brain perfusion SPECT using (99m)Tc-ethylcysteinate dimer was performed in 52 healthy men, 18-86 y old. The regional cerebral blood flow (rCBF) was noninvasively measured using graphical analysis. SPECT images were corrected for PVEs using gray-matter volume, which was segmented from coregistered MR images and convoluted with spatial resolution of SPECT scanners. Absolute rCBF data were measured using a 3-dimensional (3D) stereotactic template for regions of interest on anatomically standardized SPECT. We examined correlation of advancing age with rCBF before and after the PVE correction. To validate the correction method for PVEs, a Hoffman 3D brain phantom experiment was also performed. RESULTS: The PVE correction remarkably reduced the coefficient of variation for SPECT counts in the whole phantom. The PVE correction made the rCBF distribution more homogeneous throughout the brain with less intersubject variation than the original distribution. There were significant negative correlations between age and adjusted rCBF in the bilateral perisylvian and medial frontal areas. These correlations remained significant after the PVE correction. Instead of a positive correlation in the medial temporal structures between age and adjusted rCBF before the PVE correction, the sensorimotor and parietal areas mainly showed positive correlations after the correction. CONCLUSION: SPECT data reflect both brain volume loss and functional changes. Use of the PVE correction in brain perfusion SPECT provides a more accurate determination of rCBF even in healthy volunteers.

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.

Detection and characterization of a rat parotid gland protein kinase that catalyzes phosphorylation of matured destrin at Ser-2.

Destrin, an actin-binding protein, is partly phosphorylated at Ser-2 (numbering on the matured form) in the resting rat parotid gland, and beta-adrenergic or cholinergic stimulation of this gland induces its dephosphorylation. In this study, we searched for the protein kinase involved in phosphorylation of destrin. We developed an assay method for the kinase, using an antibody specific to destrin phosphorylated at Ser-2, and detected the kinase in the rat parotid homogenate. This enzyme was predominantly (93%) present in the soluble fraction, and the enzyme in this fraction was characterized. It had an optimum pH at 6.8 and required 3-5 mM Mg2+ for its maximum activity. Ca2+ (1 mM) had no effect whereas Mn2+ (5 mM) inhibited the enzyme activity by 75%. The apparent Km values for destrin and ATP were 92 microg/ml and 170 microM, respectively. GTP was an inefficient phosphate donor, and cAMP had no effect. Heat-denatured destrin was poorly phosphorylated. Two-dimensional PAGE analysis of destrin phosphorylated with the soluble fraction indicated that it was exclusively phosphorylated at Ser-2. None of the protein kinase inhibitors tested here was specific to this enzyme. At 1 mM, ML-7, Y-27632, KN-93, HA-1077, H-7, and H-8 inhibited the activity by 88, 61, 58, 49, 46, and 42%, respectively. Staurosporine (2 microM) and H-89 (50 microM) inhibited the activity by 48 and 33%, respectively. Heparin (30 microg/ml) had no effect. These results suggest that the rat parotid gland contains a novel, constitutively active, soluble protein kinase catalyzing specific phosphorylation of destrin at Ser-2.

Prediction of outcomes in MCI with (123)I-IMP-CBF SPECT: a multicenter prospective cohort study.

OBJECTIVE: The multicenter prospective cohort study (Japan Cooperative SPECT Study on Assessment of Mild Impairment of Cognitive Function: J-COSMIC) aimed to examine the value of (123)I-N-isopropyl-4-iodoamphetamine cerebral blood flow (IMP-CBF) SPECT in regards to early diagnosis of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI). METHODS: Three hundred and nineteen patients with amnestic MCI at 41 participating institutions each underwent clinical and neuropsychological examinations and (123)I-IMP-CBF SPECT at baseline. Subjects were followed up periodically for 3 years, and progression to dementia was evaluated. SPECT images were classified as AD/DLB (dementia with Lewy bodies) pattern and non-AD/DLB pattern by central image interpretation and automated region of interest (ROI) analysis, respectively. Logistic regression analyses were used to assess whether baseline (123)I-IMP-CBF SPECT was predictive of longitudinal clinical outcome. RESULTS: Ninety-nine of 216 amnestic MCI patients (excluding 3 cases with epilepsy (n = 2) or hydrocephalus (n = 1) and 100 cases with incomplete follow-up) converted to AD within the observation period. Central image interpretation and automated ROI analysis predicted conversion to AD with 56 and 58 % overall diagnostic accuracy (sensitivity, 76 and 81 %; specificity, 39 and 37 %), respectively. Multivariate logistic regression analysis identified SPECT as a predictor, which distinguished AD converters from non-converters. The odds ratio for a positive SPECT to predict conversion to AD with automated ROI analysis was 2.5 and combining SPECT data with gender and mini-mental state examination (MMSE) further improved classification (joint odds ratio 20.08). CONCLUSIONS: (123)I-IMP-CBF SPECT with both automated ROI analysis and central image interpretation was sensitive but relatively nonspecific for prediction of clinical outcome during the 3-year follow-up in individual amnestic MCI patients. A combination of statistically significant predictors, both SPECT with automated ROI analysis and neuropsychological evaluation, may increase predictive utility.

[Brain functional imaging of frontotemporal lobar degeneration].

Frontotemporal lobar degeneration (FTLD) is one of the common diseases causing dementia by including degenerative changes within the brain. The clinical subtypes of FTLD comprise frontotemporal dementia (FTD), progressive nonfluent aphasia (PNFA), and semantic dementia (SD). In this review, the role of the brain functional imaging on diagnosing of FTLD is described. Regionally distinct patterns of hypoperfusion on single-photon emission computed tomography (SPECT) or hypometabolism on positron emission tomography (PET) are helpful in differentiation of FTLD, Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and corticobasal degeneration (CBD). The recently developed techniques show great promise in detecting specific neuropathological changes in dementia such as amyloid and tau pathology.

Prevalence of restless legs syndrome in a Japanese elderly population.

OBJECTIVE: To estimate the prevalence of restless leg syndrome (RLS) in elderly Japanese people by means of a population-based survey of subjects aged > or = 65 years. BACKGROUND: Studies conducted worldwide have revealed large variations in the prevalence of RLS among different populations. However, few studies have been done in Japan. METHODS: A population-based survey was carried out from 2003 to 2006 through a local healthcare project in the small town of Ajimu in a rural area of southern Japan. A Japanese translation of the questionnaire covering the four features of RLS as defined by the International RLS Study Group in 1995 was used to confirm the diagnosis of RLS. All participants aged > or = 65 years were invited to fill out the questionnaire. Subjects with positive results underwent face-to-face interviews. RESULTS: A total of 1251 persons (men, 35%; mean age, 75.0+/-6.1 years) answered the questionnaire. Of these 1251 participants, 70 (5.6%) (men, 20%; mean age, 75+/-4.9 years) answered the questions on RLS positively. Face-to-face interviews and examination confirmed the diagnosis of RLS in 12 subjects. Therefore the overall prevalence of RLS in the elderly Japanese population was estimated at 0.96%, with a higher prevalence in women (1.23%) than in men (0.46%). CONCLUSION: The overall prevalence of RLS among inhabitants of Ajimu aged > or = 65 years is 0.96%. Most of the subjects identified were women. The prevalence of RLS is lower in Japan than in studies conducted in European and North American populations.

Relationship between delusions and regional cerebral blood flow in Alzheimer's disease.

UNLABELLED: To investigate the association between delusions and cerebral functional deficits in Alzheimer's disease (AD), we evaluated probable AD patients with and without delusions. METHODS: Functional brain imaging was performed by single photon emission computed tomography with technetium-99m-labeled ethyl cysteinate dimer (99mTc-ECD) in 64 AD patients and 76 age-matched normal healthy volunteers. SPECT data were analyzed by statistical parametric mapping. RESULTS: In AD patients, no differences were found in age and cognitive activities between those with (n = 25) and without (n = 39) delusions. Compared with normal healthy volunteers, AD patients had significantly decreased perfusion in the posterior cingulate gyri, precunei, and parietal association cortex. Moreover, in the patients with delusions, perfusion was significantly decreased in the frontal lobe with right side dominance. In the comparison between the patients with and without delusions, the patients with delusions had significantly decreased perfusion in the prefrontal cortex, anterior cingulate gyri, inferior to middle temporal cortices, and parietal cortex of the right hemisphere (p < 0.01). CONCLUSION: The functional deficits in the right hemisphere may be the cause of delusions in AD.

Relationship between antisocial behavior and regional cerebral blood flow in frontotemporal dementia.

OBJECTIVE: To examine the relationship between antisocial behaviors and reduction of regional cerebral blood flow (rCBF) in patients with frontotemporal dementia (FTD). METHODS: Brain perfusion single photon emission computed tomography (SPECT) was performed in 22 patients with FTD and 76 age-matched healthy volunteers. The statistical analysis was conducted using the SPM99 software. The antisocial behavioral symptoms were assessed independently by three geriatric psychiatrists, who had not been given the information of the SPECT images. RESULTS: Compared with normal controls, FTD patients showed significant reduction of rCBF in the widespread frontal cortical areas. The correlation analysis showed that antisocial behavioral symptoms are associated with reduction of rCBF in the orbitofrontal cortex. CONCLUSION: The functional decline of orbitofrontal cortex is related to antisocial behavioral symptoms in patients with FTD.

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

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

Brain SPET abnormalities in Alzheimer's disease before and after atrophy correction.

The aim of this study was to determine which brain structures show the greatest influence of partial volume effects (PVE) in single-photon emission tomography (SPET) studies on Alzheimer's disease (AD). Brain perfusion SPET was performed in 30 patients with probable AD and 62 age-matched healthy volunteers. SPET images were corrected for PVE using grey matter volume segmented from magnetic resonance images. The most prominent changes after PVE correction were observed in the medial temporal structures. The PVE correction revealed a selective decrease in regional cerebral blood flow (rCBF) in the parahippocampal gyrus of AD without rCBF decreases in the hippocampus, which had been observed before correction. This correction seems to be essential in order to achieve accurate measurements of rCBF in SPET, which has limited spatial resolution.