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Purpose: Predicting progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD) or dementia with Lewy bodies (DLB) is important. We evaluated morphological and functional differences between MCI with Lewy bodies (MCI-LB) and MCI due to AD (MCI-AD), and a method for differentiating between these conditions using brain MRI and brain perfusion SPECT., Methods: A continuous series of 101 subjects, who had visited our memory clinic and met the definition of MCI, were enrolled retrospectively. They were consisted of 60 MCI-LB and 41 MCI-AD subjects. Relative cerebral blood flow (rCBF) on SPECT images and relative brain atrophy on MRI images were evaluated. We performed voxel-based analysis and visually inspected brain perfusion SPECT images for regional brain atrophy, occipital hypoperfusion and the cingulate island sign (CIS), for differential diagnosis of MCI-LB and MCI-AD., Results: MRI showed no significant differences in regional atrophy between the MCI-LB and MCI-AD groups. In MCI-LB subjects, occipital rCBF was significantly decreased compared with MCI-AD subjects (p < 0.01, family wise error [FWE]-corrected). Visual inspection of occipital hypoperfusion had sensitivity, specificity, and accuracy values of 100%, 73.2% and 89.1%, respectively, for differentiating MCI-LB and MCI-AD. Occipital hypoperfusion was offered higher diagnostic utility than the CIS., Conclusions: The occipital lobe was the region with significantly decreased rCBF in MCI-LB compared with MCI-AD subjects. Occipital hypoperfusion on brain perfusion SPECT may be a more useful imaging biomarker than the CIS for visually differentiating MCI-LB and MCI-AD., (© 2023. The Author(s) under exclusive licence to Japan Radiological Society.)

Background: Aggression, a common symptom of Alzheimer's disease (AD), can impose a significant burden on caregivers, necessitating early institutionalization., Objective: The current study examined the neural basis of aggression and its expression mechanism, to advance the development of effective treatment strategies for aggression in patients with AD., Methods: The study sample included 257 patients; 180 were diagnosed with AD and 77 with amnestic mild cognitive impairment (aMCI). Factor analysis of the neuropsychiatric inventory (NPI) aggression scores was performed, and the correlation between each factor and cerebral blood flow (CBF) was examined via diagnosis of AD or aMCI using statistical parametric mapping., Results: Refusal of care was correlated with reduced CBF in the right hippocampus of patients with AD while no specific related regions could be identified in patients with aMCI. Violent behavior was associated with decreased CBF in the right temporal pole and medial frontal lobe of patients with AD and aMCI., Conclusions: These findings suggest that aggression, measured using NPI includes two distinct symptoms, refusal of care and violent behavior, having different underlying neural bases.

Background: Neuropsychiatric symptoms (NPS) in patients with dementia lead to caregiver burdens and worsen the patient's prognosis. Although many neuroimaging studies have been conducted, the etiology of NPS remains complex. We hypothesize that brain structural asymmetry could play a role in the appearance of NPS., Objective: This study explores the relationship between NPS and brain asymmetry in patients with Alzheimer's disease (AD)., Methods: Demographic and MRI data for 121 mild AD cases were extracted from a multicenter Japanese database. Brain asymmetry was assessed by comparing the volumes of gray matter in the left and right brain regions. NPS was evaluated using the Neuropsychiatric Inventory (NPI). Subsequently, a comprehensive assessment of the correlation between brain asymmetry and NPS was conducted., Results: Among each NPS, aggressive NPS showed a significant correlation with asymmetry in the frontal lobe, indicative of right-side atrophy (r = 0.235, p = 0.009). This correlation remained statistically significant even after adjustments for multiple comparisons (p < 0.01). Post-hoc analysis further confirmed this association (p < 0.05). In contrast, no significant correlations were found for other NPS subtypes, including affective and apathetic symptoms., Conclusions: The study suggests frontal lobe asymmetry, particularly relative atrophy in the right hemisphere, may be linked to aggressive behaviors in early AD. These findings shed light on the neurobiological underpinnings of NPS, contributing to the development of potential interventions.

Purpose: To determine the association between occipital amyloid-PET uptake and neurocognitive performance in Alzheimer's disease (AD)., Materials and Methods: Fifty-eight participants with normal aged, mild cognitive impairment (MCI) due to AD and AD subjects who underwent F-18 florbetapir brain PET/CT scans were divided into four groups (A, normal; B, MCI; C, mild AD; and D, moderate/severe AD). Semiquantitative analyses of SUVR images were performed. The differences between groups and the correlations between florbetapir uptake and Thai Mental State Examination (TMSE) scores were determined. Significant differences were defined using a P < 0.001, uncorrected, or a P < 0.05, FWE for the voxel-based analyses with Statistical Parametric Mapping (SPM)., Results: There was a slightly higher florbetapir uptake in the precuneus, parietal, and occipital association cortices in Group B > A. The occipital florbetapir uptake in Groups C and D was significantly higher than in Group A, in addition to the precuneus, anterior cingulate, posterior cingulate, temporoparietal, and frontal cortices. There was a strong negative correlation between TMSE scores and florbetapir uptake in the occipital lobe., Conclusions: Occipital amyloid uptake is associated with clinically advanced AD, and is inversely correlated with neurocognitive performance and may be useful for evaluating AD severity., (© 2021. Japan Radiological Society.)

Background: Alzheimer's disease is a neurodegenerative disease involving the deposition of pathologic amyloid-β and tau protein in the cerebral cortex. Alzheimer's disease is commonly characterized by progressive impairment of recent memory. Primary progressive aphasia is also often observed in patients with Alzheimer's disease. Moreover, language-associated symptoms, such as primary progressive aphasia, are diverse and varied in Alzheimer's disease. However, nonfluent/agrammatic variant primary progressive aphasia is not generally considered a symptom of Alzheimer's disease. To date, there has been no longitudinal study of primary progressive aphasia in Japanese-speaking patients or in patients speaking other languages with pathologically diagnosed Alzheimer's disease. Here we present a longitudinal study of primary progressive aphasia in a Japanese patient pathologically diagnosed with Alzheimer's disease., Case Presentation: A 75-year-old Japanese man, whose wife reported that his memory was impaired, also suffered from suspected aphasia. He was pathologically diagnosed with Alzheimer's disease using 11 C-Pittsburgh compound-B positron emission tomography and 18 F-THK5351 positron emission tomography. Based on clinical observation and the results of the Japanese standard language test of aphasia, he was also diagnosed with nonfluent/agrammatic variant primary progressive aphasia. During the subsequent 2 years, his cognitive impairment, aphasia, and behavioral and psychological symptoms of dementia progressed. Furthermore, progression of pathologic amyloid-β and tau protein deposition was revealed through 11 C-Pittsburgh compound-B positron emission tomography and 18 F-THK5351 positron emission tomography. Although the results of [ 123 I] iodoamphetamine single-photon emission computed tomography suggested corticobasal degeneration, this was not observed on the [ 123 I] FP-CIT single-photon emission computed tomography (SPECT) (DaTscan). A previous study had reported that Alzheimer's disease with a nonfluent/agrammatic variant primary progressive aphasia was accompanied by corticobasal degeneration; however, this was not true in our case., Conclusions: This is possibly the first longitudinal study of nonfluent/agrammatic variant primary progressive aphasia in a Japanese-speaking patient with pathologically diagnosed Alzheimer's disease, but without corticobasal degeneration.

Background: The Logan graphical analysis (LGA) algorithm is widely used to quantify receptor density for parametric imaging in positron emission tomography (PET). Estimating receptor density, in terms of the non-displaceable binding potential (BP ND ), from the LGA using the ordinary least-squares (OLS) method has been found to be negatively biased owing to noise in PET data. This is because OLS does not consider errors in the X-variable (predictor variable). Existing bias reduction methods can either only reduce the bias slightly or reduce the bias accompanied by increased variation in the estimates. In this study, we addressed the bias reduction problem by applying a different regression method., Methods: We employed least-squares cubic (LSC) linear regression, which accounts for errors in both variables as well as the correlation of these errors. Noise-free PET data were simulated, for 11 C-carfentanil kinetics, with known BP ND values. Statistical noise was added to these data and the BP ND s were re-estimated from the noisy data by three methods, conventional LGA, multilinear reference tissue model 2 (MRTM2), and LSC-based LGA; the results were compared. The three methods were also compared in terms of beta amyloid (A β) quantification of 11 C-Pittsburgh compound B brain PET data for two patients with Alzheimer's disease and differing A β depositions., Results: Amongst the three methods, for both synthetic and actual data, LSC was the least biased, followed by MRTM2, and then the conventional LGA, which was the most biased. Variations in the LSC estimates were smaller than those in the MRTM2 estimates. LSC also required a shorter computational time than MRTM2., Conclusions: The results suggest that LSC provides a better trade-off between the bias and variability than the other two methods. In particular, LSC performed better than MRTM2 in all aspects; bias, variability, and computational time. This makes LSC a promising method for BP ND parametric imaging in PET studies.

Objective: This study aims to develop an algorithm named AutoRef to delineate a reference region for quantitative PET amyloid imaging., Methods: AutoRef sets the reference region automatically using a distinguishing feature in the kinetics of reference region. This is reflected in the shapes of the tissue time activity curve. A statistical shape recognition algorithm of the gaussian mixture model is applied with considering spatial and temporal information on a reference region. We evaluate the BP ND with manually set reference region and AutoRef using 86 cases (43 positive cases, 10 equivocal cases, and 33 negative cases) of dynamically scanned 11 C-Pittsburgh Compound-B., Results: From the Bland-Altman plot, the difference between two BP ND is 0.099 ± 0.21 as standard deviation, and no significant systematic error is observed between the BP ND with AutoRef and with manual definition of a reference region. Although a proportional error is detected, it is smaller than the 95% limits of agreement. Therefore, the proportional error is negligibly small., Conclusions: AutoRef presents the same performance as the manual definition of the reference region. Further, since AutoRef is more algorithmic than the ordinary manual definition of the reference region, there are few operator-oriented uncertainties in AutoRef. We thus conclude that AutoRef can be applied as an automatic delineating algorithm for the reference region in amyloid imaging.

Objective: The objectives of the present study were to investigate (1) whether trinary visual interpretation of amyloid positron emission tomography (PET) imaging (negative/equivocal/positive) reflects quantitative amyloid measurements and the time course of 11 C-Pittsburgh compound B (PiB) amyloid accumulation, and (2) whether visually equivocal scans represent an early stage of the Alzheimer's disease (AD) continuum in terms of an intermediate state of quantitative amyloid measurements and the changes in amyloid accumulation over time., Methods: From the National Bioscience Database Center Human Database of the Japanese Alzheimer's Disease Neuroimaging Initiative, we selected 133 individuals for this study including 33 with Alzheimer's disease dementia (ADD), 52 with late mild cognitive impairment (LMCI), and 48 cognitively normal (CN) subjects who underwent clinical assessment, PiB PET, and structural magnetic resonance imaging (MRI) with 2 or 3-years of follow-up. Sixty-eight of the 133 individuals underwent cerebrospinal fluid amyloid-β 1-42 (CSF-Ab 42 ) analysis at baseline. The standard uptake value ratio (SUVR) of PiB PET was calculated with a method using MRI at each visit. The cross-sectional values, longitudinal changes in SUVR, and baseline CSF-Ab 42 were compared among groups, which were categorized based on trinary visual reads of amyloid PET (negative/equivocal/positive)., Results: From the trinary visual interpretation of the PiB PET images, 55 subjects were negative, 8 were equivocal, and 70 were positive. Negative interpretation was most frequent in the CN group (70.8/10.4/18.8%: negative/equivocal/positive), and positive was most frequent in the LMCI group (34.6/1.9/63.5%) and in the ADD group (9.1/6.1/84.8%). The baseline SUVRs were 1.08 ± 0.06 in the negative group, 1.23 ± 0.15 in the equivocal group, and 1.86 ± 0.31 in the positive group (F = 174.9, p < 0.001). The baseline CSF-Ab 42 level was 463 ± 112 pg/mL in the negative group, 383 ± 125 pg/mL in the equivocal group, and 264 ± 69 pg/mL in the positive group (F = 37, p < 0.001). Over the 3-year follow-up, annual changes in SUVR were - 0.00 ± 0.02 in the negative group, 0.02 ± 0.02 in the equivocal group, and 0.04 ± 0.07 in the positive group (F = 8.4, p < 0.001)., Conclusions: Trinary visual interpretation (negative/equivocal/positive) of amyloid PET imaging reflects quantitative amyloid measurements evaluated with PET and the CSF amyloid test as well as the amyloid accumulation over time evaluated with PET over 3 years. Subjects in the early stage of the AD continuum could be identified with an equivocal scan, because they showed intermediate quantitative amyloid PET, CSF measurements, and the amyloid accumulation over time.

Background: Amyloid-β (Aβ) accumulation in brain of patients with suspected Alzheimer's disease (AD) can be assessed by positron emission tomography (PET) in vivo. While visual classification prevails in the clinical routine, semiquantitative PET analyses may enable more reliable evaluation of cases with a visually uncertain, borderline Aβ accumulation., Objective: We evaluated different analysis approaches (visual/semiquantitative) to find the most accurate and sensitive interpretation of Aβ-PET for predicting risk of progression from mild cognitive impairment (MCI) to AD., Methods: Based on standard uptake value (SUV) ratios of a cortical-composite volume of interest of 18F-AV45-PET from MCI subjects (n = 396, ADNI database), we compared three different reference region (cerebellar grey matter, CBL; brainstem, BST; white matter, WM) normalizations and the visual read by receiver operator characteristics for calculating a hazard ratio (HR) for progression to Alzheimer's disease dementia (ADD)., Results: During a mean follow-up time of 45.6±13.0 months, 28% of the MCI cases (110/396) converted to ADD. Among the tested methods, the WM reference showed best discriminatory power and progression-risk stratification (HRWM of 4.4 [2.6-7.6]), but the combined results of the visual and semiquantitative analysis with all three reference regions showed an even higher discriminatory power., Conclusion: A multi-analytical composite of visual and semiquantitative reference tissue analyses of 18F-AV45-PET gave improved risk stratification for progression from MCI to ADD relative to performance of single read-outs. This optimized approach is of special interest for prospective treatment trials, which demand a high accuracy.

ABSTRACTTau deposits in Alzheimer's disease and corticobasal syndrome have been reported using 18F-THK-5351 positron emission tomography (PET). To our knowledge, our study is the first to demonstrate tau deposits in patients with frontotemporal lobe degeneration (FTLD), using 18F-THK-5351 PET. This case report presents two patients, both of whom showed positive Tau deposition using 18F-THK-5351 PET. One patient was diagnosed with semantic variant primary progressive aphasia (PPA) and the other diagnosed with logopenic variant PPA. Our results suggest an association in the pathology of Alzheimer's disease, corticobasal syndrome, and FTLD, and could plan more effective clinical care in advance.

To facilitate clinical trials of disease-modifying therapies for Alzheimer's disease, which are expected to be most efficacious at the earliest and mildest stages of the disease, supportive biomarker information is necessary. The only validated methods for identifying amyloid-β deposition in the brain-the earliest pathological signature of Alzheimer's disease-are amyloid-β positron-emission tomography (PET) imaging or measurement of amyloid-β in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable. Despite much effort, to our knowledge, no study has validated the clinical utility of blood-based amyloid-β markers. Here we demonstrate the measurement of high-performance plasma amyloid-β biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-β precursor protein (APP) 669-711 /amyloid-β (Aβ) 1-42 and Aβ 1-40 /Aβ 1-42 ratios, and their composites, to predict individual brain amyloid-β-positive or -negative status was determined by amyloid-β-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using 11 C-labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer's disease. All test biomarkers showed high performance when predicting brain amyloid-β burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-β-PET burden and levels of Aβ 1-42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-β burden at an individual level. These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.

Late-life depression, even when of subsyndromal severity, has shown strong associations with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Preclinical studies have suggested that serotonin selective reuptake inhibitors (SSRIs) can attenuate amyloidogenesis. Therefore, we aimed to investigate the effect of SSRI medication on amyloidosis and grey matter volume in subsyndromal depressed subjects with MCI and AD during an interval of two years. 256 cognitively affected subjects (225 MCI/ 31 AD) undergoing [18F]-AV45-PET and MRI at baseline and 2-year follow-up were selected from the ADNI database. Subjects with a positive depression item (DEP(+); n = 73) in the Neuropsychiatric Inventory Questionnaire were subdivided to those receiving SSRI medication (SSRI(+); n = 24) and those without SSRI treatment (SSRI(-); n = 49). Longitudinal cognition (Δ-ADAS), amyloid deposition rate (standardized uptake value, using white matter as reference region (SUVRWM), and changes in grey matter volume were compared using common covariates. Analyses were performed separately in all subjects and in the subgroup of amyloid-positive subjects. Cognitive performance in DEP(+)/SSRI(+) subjects (Δ-ADAS: -5.0%) showed less deterioration with 2-year follow-up when compared to DEP(+)/SSRI(-) subjects (Δ-ADAS: +18.6%, p < 0.05), independent of amyloid SUVRWM at baseline. With SSRI treatment, the progression of grey matter atrophy was reduced (-0.9% versus -2.7%, p < 0.05), notably in fronto-temporal cortex. A slight trend towards lower amyloid deposition rate was observed in DEP(+)/SSRI(+) subjects versus DEP(+)/SSRI(-). Despite the lack of effect to amyloid PET, SSRI medication distinctly rescued the declining cognitive performance in cognitively affected patients with depressive symptoms, and likewise attenuated grey matter atrophy.

Purpose: The aim of this study was to assess the inter-rater variability of the visual interpretation of 11 C-PiB PET images regarding the positivity/negativity of amyloid deposition that were obtained in a multicenter clinical research project, Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI). The results of visual interpretation were also compared with a semi-automatic quantitative analysis using mean cortical standardized uptake value ratio to the cerebellar cortex (mcSUVR)., Methods: A total of 162 11 C-PiB PET scans, including 45 mild Alzheimer's disease, 60 mild cognitive impairment, and 57 normal cognitive control cases that had been acquired as J-ADNI baseline scans were analyzed. Based on visual interpretation by three independent raters followed by consensus read, each case was classified into positive, equivocal, and negative deposition (ternary criteria) and further dichotomized by merging the former two (binary criteria)., Results: Complete agreement of visual interpretation by the three raters was observed for 91.3% of the cases (Cohen κ = 0.88 on average) in ternary criteria and for 92.3% (κ = 0.89) in binary criteria. Cases that were interpreted as visually positive in the consensus read showed significantly higher mcSUVR than those visually negative (2.21 ± 0.37 vs. 1.27 ± 0.09, p < 0.001), and positive or negative decision by visual interpretation was dichotomized by a cut-off value of mcSUVR = 1.5. Significant positive/negative associations were observed between mcSUVR and the number of raters who evaluated as positive (ρ = 0.87, p < 0.0001) and negative (ρ = -0.85, p < 0.0001) interpretation. Cases of disagreement among raters showed generally low mcSUVR., Conclusions: Inter-rater agreement was almost perfect in 11 C-PiB PET scans. Positive or negative decision by visual interpretation was dichotomized by a cut-off value of mcSUVR = 1.5. As some cases of disagreement among raters tended to show low mcSUVR, referring to quantitative method may facilitate correct diagnosis when evaluating images of low amyloid deposition.

Using 11C-Pittsburgh compound B (PiB)-PET and MRI volume data, we investigated whether white matter (WM) PiB uptake in Alzheimer's disease (AD) brain is larger than that of cortical PiB uptake-negative (PiB-negative) brain. Forty-five subjects who underwent both PiB-PET and MRI were included in the study (32 AD patients with cortical PiB-positive and 13 cortical amyloid -negative patients). Individual areas of gray matter (GM) and WM were segmented, then regional GM and WM standard uptake value ratio (SUVR) normalized to cerebellar GM with partial volume effects correction was calculated. Three regional SUVRs except WM in the centrum semiovale in the AD group were significantly larger than those in the PiB-negative groups. Frontal WM SUVR in the AD group vs frontal WM SUVR in the PiB-negative group was 2.57 ± 0.55 vs 1.64 ± 0.22; parietal, 2.50 ± 0.52 vs 1.74 ± 0.22; posterior cingulate, 2.84 ± 0.59 vs 1.73 ± 0.22; and WM in the centrum semiovale, 2.21 ± 0.53 vs 2.42 ± 0.36, respectively. We found that PiB uptake in AD brain is significantly larger than that in PiB-negative brain in the frontal, parietal and posterior cingulate subcortical WM, except in the centrum semiovale.

Objective: Alzheimer' disease (AD) is characterized by increase of cortical amyloid deposition in prodromal stage and subsequent decrease of cerebral glucose metabolism as disease progresses. The present study introduces the voxel-wise metabolism to amyloid deposits ratio (MAR) image and to evaluate its reliability for the diagnosis of AD., Methods: Consecutive one-hundred and forty-three subjects with AD and 181 normal subjects who underwent both 18F-FDG PET and 18F-florbetapir (AV-45) PET at baseline were included to this study from the database of Alzheimer's disease neuroimaging initiative (ADNI). After normalizing to a standard stereotactic space, the MAR image was created by dividing each FDG-PET image by corresponding AV-45 PET image using with voxel-wise inter-image computation. We examined voxel wise comparison in the MAR images between AD subjects and normal subjects and compared the diagnostic performances between the MAR image and FDG-PET and AV-45 image., Results: In the voxel wise comparison, the MAR images of AD subjects exhibited severe and extensive decrease compared with normal subjects in the affected region in both FDG-PET and AV-45, especially in the precuneus /posterior cingulate. The highest t-value was equivalent to FDG-PET and the voxel extent was much greater than the other images. In the ROI analysis, the diagnostic accuracies were 82.6% (sensitivity: 86.7%, specificity: 79.5%), 80.7% (sensitivity: 77%, specificity: 83.4%), and 78.8% (sensitivity: 75.2%, specificity: 81.5%) for the MAR image, FDG-PET, and AV-45, respectively. AUC for the MAR image was 0.904 (95%CI: 0.867-0.942), and was larger than those for FDG-PET (AUC: 0.884, 95%CI: 0.843-0.926), and AV-45 (AUC: 0.847, 95%CI: 0.798-0.897)., Conclusion: MAR image reflected not only amyloid deposition but the cerebral glucose metabolisms and successfully classified the subjects with AD. These data suggest that the MAR image might be a more proper appropriate diagnostic marker for AD reflecting cerebral metabolisms and amyloid deposition.

Purpose: There is evidence that some cases of patients with dementia with Lewy bodies (DLB) can demonstrate Alzheimer disease (AD) like reduced glucose metabolism without amyloid deposition. The aim of this study was to clarify whether regional hypometabolism is related to amyloid deposits in the DLB brain and measure the degree of regional hypometabolism., Methods: Ten consecutive subjects with DLB and 10 AD patients who underwent both Pittsburgh compound B (PiB)-PET and (18)F-fluoro-2-deoxyglucose (FDG)-PET were included in this study. Regional standardized uptake value ratio (SUVR)s normalised to cerebellar cortices were calculated in the FDG- and PiB-PET images., Results: All AD patients and five DLB patients showed amyloid deposits (PiB positive). In the DLB group the parietotemporal and occipital metabolism were significantly lower than those in the AD group but there was no difference between the posterior cingulate hypometabolism between DLB and AD groups. There were no differences in regional glucose metabolism between PiB positive and negative DLB patients., Conclusions: In the DLB brain, it is suggested that decreased regional glucose metabolism is unrelated to amyloid deposits, although the hypometabolic area overlaps with the AD hypometabolic area and the degree of parietotemporal and occipital hypometabolism in DLB brain is much larger than that in AD brain.

Purpose: Due to increasing numbers of patients with dementia, more physicians who do not specialize in brain nuclear medicine are being asked to interpret SPECT images of cerebral blood flow. We conducted a multicenter study to determine whether a computer-assisted diagnostic system Z-score summation analysis method (ZSAM) using three-dimensional stereotactic surface projections (3D-SSP) can differentiate Alzheimer's disease (AD)/dementia with Lewy bodies (DLB) and non-AD/DLB in institutions using various types of gamma cameras., Method: We determined the normal thresholds of Z-sum (summed Z-score) within a template region of interest for each single photon emission computed tomography (SPECT) device and then compared them with the Z-sums of patients and calculated the accuracy of the differential diagnosis by ZSAM. We compared the diagnostic accuracy between ZSAM and visual assessment., Patients: We enrolled 202 patients with AD (mean age, 76.8 years), 40 with DLB (mean age 76.3 years) and 36 with non-AD/DLB (progressive supranuclear palsy, n = 10; frontotemporal dementia, n = 20; slowly progressive aphasia, n = 2 and one each with idiopathic normal pressure hydrocephalus, corticobasal degeneration, multiple system atrophy and Parkinson's disease) who underwent N-isopropyl-p-[(123)I] iodoamphetamine cerebral blood flow SPECT imaging at each participating institution., Results: The ZSAM sensitivity to differentiate between AD/DLB and non-AD/DLB in all patients, as well as those with mini-mental state examination scores of ≥24 and 20-23 points were 88.0, 78.0 and 88.4 %, respectively, with specificity of 50.0, 44.4 and 60.0 %, respectively. The diagnostic accuracy rates were 83.1, 72.9 and 84.2 %, respectively. The areas under receiver operating characteristics curves for visual inspection by four expert raters were 0.74-0.84, 0.66-0.85 and 0.81-0.93, respectively, in the same patient groups. The diagnostic accuracy rates were 70.9-89.2 %, 50.9-84.8 % and 76.2-93.1 %, respectively., Conclusion: The diagnostic accuracy of ZSAM to differentiate AD/DLB from other types of dementia or degenerative diseases regardless of severity was equal to that of visual assessment by expert raters even across several institutions. These findings suggested that ZSAM could serve as a supplementary tool to help expert evaluators who differentially diagnose dementia from SPECT images by visual assessment.

Objective: To determine the optimal accumulation time for three-dimensional positron emission tomography (3D-PET) with (18)F-2-fluoro-2-deoxy-D-glucose ((18)F-FDG) to detect the brain uptake pattern typical of Alzheimer's disease (AD)., Methods: Patients with mild AD or amnestic mild cognitive impairment (MCI) and normal control subjects were recruited in the Japanese Alzheimer's disease neuroimaging initiative and examined with a PET scan during the 30-60 min after FDG injection. Three independent blinded experts interpreted the 30- to 60-min sum images, and images of patients with AD and MCI presenting AD patterns and normal subjects presenting normal patterns were used in the analysis. Early-scan (ES) and late-scan (LS) images were obtained from the data acquired at 30-35 min and 55-60 min after the injection, respectively. Separate target regions of interest (ROI) for ES and LS were defined as areas of significant reductions in the posterior cingulate and parietotemporal lobe in both hemispheres from the results of an initial cohort with 21 patients (AD 16, MCI 5) and 19 controls. A subsequent sample of 36 (AD 9, MCI 27) patients and 38 controls were used to compare the diagnostic capability of ES and LS using Z scores within the target ROI in individual statistical parametric mapping analysis., Results: Compared to LS, ES showed lower activity in the frontal lobes and higher activity in the venous sinus than LS; however, the diagnostic capability of ES and LS did not significantly differ (sensitivity 0.97 and 0.97, specificity 0.82 and 0.84, area under the receiver-operating characteristic curve 0.96 and 0.97, respectively)., Conclusions: For a qualitative diagnosis of the AD pattern in 3D FDG-PET, results of ES were equivalent to those of LS. ES may be an option to shorten the entire PET procedure time, particularly in diagnosing early stages of AD.

Among the various disorders manifesting dementia, gait disturbance, and urinary incontinence in the elderly population, idiopathic normal pressure hydrocephalus (iNPH) is becoming of great importance. After the publication of the first edition of the Guidelines for Management of Idiopathic Normal Pressure Hydrocephalus in 2004 (the English version was published in 2008), clinical awareness of iNPH has risen dramatically, and the number of shunt surgeries has increased rapidly across Japan. Clinical and basic research on iNPH has increased significantly, and more high-level evidence has since been generated. The second edition of the Japanese Guidelines was thus published in July 2011, to provide a series of timely evidence-based recommendations related to iNPH. The revision of the Guidelines has been undertaken by a multidisciplinary expert working group of the Japanese Society of Normal Pressure Hydrocephalus in conjunction with the Japanese Ministry of Health, Labour and Welfare research project on "Studies on the epidemiology, pathophysiology, and treatment of normal pressure hydrocephalus." This English version of the second edition of the Guidelines was made to share these ideas with the international community and to promote international research on iNPH.

Purpose: To develop a computer-assisted automated diagnostic system to distinguish among Alzheimer disease (AD), dementia with Lewy bodies (DLB), and other degenerative disorders in patients with mild dementia., Methods: Single photon emission computed tomography (SPECT) images with injection of N-Isopropyl-p-[(123)I]iodoamphetamine (IMP) were obtained from patients with mild degenerative dementia. First, datasets from 20 patients mild AD, 15 patients with dementia with DLB, and 17 healthy controls were used to develop an automated diagnosing system based on three-dimensional stereotactic surface projections (3D-SSP). AD- and DLB-specific regional templates were created using 3D-SSP, and critical Z scores in the templates were established. Datasets from 50 AD patients, 8 DLB patients, and 10 patients with non-AD/DLB type degenerative dementia (5 with frontotemporal dementia and 5 with progressive supranuclear palsy) were then used to test the diagnostic accuracy of the optimized automated system in comparison to the diagnostic interpretation of conventional IMP-SPECT images. These comparisons were performed to differentiate AD and DLB from non-AD/DLB and to distinguish AD from DLB. A receiver operating characteristic (ROC) analysis was performed., Results: The area under the ROC curve (Az) and the accuracy of the automated diagnosis system were 0.89 and 82%, respectively, for AD/DLB vs. non-AD/DLB patients, and 0.70 and 65%, respectively, for AD vs. DLB patients. The mean Az and the accuracy of the visual inspection were 0.84 and 77%, respectively, for AD/DLB vs. non-AD/DLB patients, and 0.70 and 65%, respectively, for AD vs. DLB patients. The mean Az and the accuracy of the combination of visual inspection and this system were 0.96 and 91%, respectively, for AD/DLB vs. non-AD/DLB patients, and 0.70 and 66%, respectively, for AD vs. DLB patients., Conclusion: The system developed in the present study achieved as good discrimination of AD, DLB, and other degenerative disorders in patients with mild dementia as the commonly performed visual inspection of conventional SPECT images. A combination of visual inspection and this system is helpful in the differential diagnosis of patients with mild dementia.

The utility of measuring the corpus callosal angle (CA) for the diagnosis of idiopathic normal pressure hydrocephalus (INPH) was investigated. Three-dimensional magnetic resonance imaging (MRI) was performed in 34 INPH patients, 34 Alzheimer's disease (AD) patients, and 34 normal control (NC) subjects. Measurement of the CA on the coronal MR images of the posterior commissure perpendicular to the anteroposterior commissure plane was performed for all subjects. The CA of the INPH group (mean +/- SD, 66 +/- 14 degrees) was significantly smaller than those of the AD (104 +/- 15 degrees) and NC (112 +/- 11 degrees) groups. When using the threshold of the mean - 2SD value of the NC group (= 90 degrees), an accuracy of 93%, sensitivity of 97%, and specificity of 88% were observed for discrimination of INPH from AD patients. Measuring the CA helps in differentiating INPH patients from AD and normally aged subjects.

Purpose: To evaluate a fully automatic computer-assisted diagnostic system for mild dementia with Lewy bodies (DLB), permitting distinction from mild Alzheimer's disease (AD)., Methods: Using 18F-fluorodeoxyglucose and positron emission tomography (FDG-PET), glucose metabolic images were obtained from mild DLB and mild AD patients. Two groups consisting of 16 mild DLB patients and 21 mild AD patients were recruited for diagnostic evaluation between mild DLB and mild AD. The mean age+/-SD of the mild DLB group and the mild AD group was 74.3+/-4.9 and 71.7+/-2.1 years, respectively, and the mean scores of the MMSE for the mild DLB and the mild AD group were 21.7+/-1.9 and 23.1+/-2.1, respectively. A receiver operating characteristic (ROC) analysis was performed to compare the diagnostic performance, in terms of discrimination between DLB and AD, of conventional axial FDG-PET images inspected visually by experts and beginners with that of our fully automatic diagnosis system using the statistical brain mapping method and Z scores obtained with the DLB template., Results: The diagnostic performance of the automatic system was comparable to that of visual inspection by experts. The area under the ROC curve for the automatic diagnosis system was 0.77. The mean area under the ROC curve for visual inspection by experts and beginners was 0.76 and 0.65, respectively., Conclusion: The fully automatic differential diagnosis system for distinction between mild DLB and AD showed a similar diagnostic accuracy to visual inspection by experts. It would be a useful diagnostic tool to distinguish mild DLB from mild AD in clinical practice.

Unlabelled: The aim of this study was to investigate regional differences between morphologic and functional changes in patients with mild dementia with Lewy bodies (DLB) compared with those with Alzheimer's disease (AD)., Methods: Twenty patients with very mild DLB (mean age, 74.5 y; mean Mini-Mental State Examination [MMSE] score, 24.0), 20 patients with very mild AD (mean age, 74.1 y; mean MMSE score, 24.0), and 20 age- and sex-matched healthy volunteers (normal controls [NC]) underwent both (18)F-FDG PET and 3-dimensional spoiled gradient echo MRI. Fully automatic volumetry of the MRI data was used to obtain whole brain, hippocampal, occipital, and striatal volumes, which were compared with the results of a similar analysis of glucose metabolic data., Results: In DLB patients, volumetric data indicated a significant volume decrease in the striatum, whereas (18)F-FDG PET showed significant glucose metabolic reductions in the temporal, parietal, and frontal areas--including in the occipital lobe--compared with those in the NC group. In contrast, in AD patients, both the hippocampal volume and glucose metabolism were significantly decreased, whereas the occipital volume and metabolism were preserved., Conclusion: Comparison of very mild DLB and AD revealed different morphologic and metabolic changes occurring in the medial temporal lobes and the occipital lobe, demonstrating characteristic pathophysiologic differences between these 2 diseases.

Purpose: The aim of this study was to compare the diagnostic performance of( 18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and voxel-based morphometry (VBM) on magnetic resonance imaging (MRI) in the same group of patients with very mild Alzheimer's disease (AD)., Methods: Thirty patients with very mild AD (age 67.0+/-5.8 years; MMSE score 25.5+/-1.2, range 24-28), 32 patients with mild AD (age 67.0+/-4.5 years, MMSE score 22.1+/-0.8, range 21-23) and 60 age- and sex-matched normal volunteers underwent both FDG-PET and three-dimensional spoiled gradient echo MRI. Statistical parametric mapping was used to conduct voxel by voxel analysis and Z score mapping. First, the region of interest (ROI) maps of significant reductions in glucose metabolism and grey matter density in the mild AD patients were defined. Secondly, analysis of receiver operating characteristic (ROC) curves for Z scores in the ROI maps discriminating very mild AD patients and normal controls was performed., Results: In mild AD patients, FDG-PET indicated significant reductions in glucose metabolism in the bilateral posterior cingulate gyri and the right parietotemporal area, while VBM analysis showed a significant decrease in grey matter volume density in the bilateral amygdala/hippocampus complex, compared with the normal control group. ROC analysis showed that in very mild AD patients the accuracy of FDG-PET diagnosis was 89% and that of VBM-MRI diagnosis was 83%. The accuracy of the combination of FDG-PET and VBM-MRI diagnosis was 94%., Conclusion: In very mild AD, both FDG-PET and VBM-MRI had high accuracy for diagnosis, but FDG-PET showed slightly higher accuracy than VBM-MRI. Combination of the two techniques will yield a higher diagnostic accuracy in very mild AD by making full use of functional and morphological images.

Purpose: The purpose of this study was to design a fully automatic computer-assisted diagnostic system for early- and late-onset mild Alzheimer's disease (AD)., Methods: Glucose metabolic images were obtained from mild AD patients and normal controls using positron emission tomography (PET) and( 18)F-fluorodeoxyglucose (FDG). Two groups of 20 mild AD patients with different ages of onset were examined. A fully automatic diagnostic system using the statistical brain mapping method was established from the early-onset (EO) and late-onset (LO) groups, with mean ages of 59.1 and 70.9 years and mean MMSE scores of 23.3 and 22.8, respectively. Aged-matched normal subjects were used as controls. We compared the diagnostic performance of visual inspection of conventional axial FDG PET images by experts and beginners with that of our fully automatic diagnostic system in another 15 EO and 15 LO AD patients (mean age 58.4 and 71.7, mean MMSE 23.6 and 23.1, respectively) and 30 age-matched normal controls. A receiver operating characteristic (ROC) analysis was performed to compare data., Results: The diagnostic performance of the automatic diagnostic system was comparable with that of visual inspection by experts. The area under the ROC curve for the automatic diagnostic system was 0.967 for EO AD patients and 0.878 for LO AD patients. The mean area under the ROC curve for visual inspection by experts was 0.863 and 0.881 for the EO and LO AD patients, respectively. The mean area under the ROC curve for visual inspection by beginners was 0.828 and 0.717, respectively., Conclusion: The fully automatic diagnostic system for EO and LO AD was able to perform at a similar diagnostic level to visual inspection of conventional axial images by experts.

Objective: presenilin-2 is one of the causative genes for familial Alzheimer's disease, and the apolipoprotein E epsilon4 allele is a major genetic risk factor for late-onset and sporadic early-onset Alzheimer's disease. Polymorphism of the regulatory region of presenilin-2 has recently been reported to be associated with sporadic Alzheimer's disease in a Russian population. The purpose of this study was to determine whether Alzheimer's disease is associated with the presenilin-2 gene polymorphism and the apolipoprotein E genotype in an extended case-control study., Methods: We examined 230 patients with Alzheimer's disease, along with an equal number of age- and sex-matched controls from the same community, in a Japanese population by using a Chi-square test for homogeneity and a logistic regression analysis., Results: The presenilin-2 polymorphism frequencies were similar in early-onset Alzheimer's disease patients (0.17) and younger controls (0.15), and in late-onset Alzheimer's disease (0.20) and elderly controls (0.20). We found no evidence for an association between the presenilin-2 polymorphism and the apolipoprotein E epsilon4 allele., Conclusions: Our results fail to support an association of presenilin-2 gene polymorphism with Alzheimer's disease. The discrepancy between our results and the results of the Russian study appear to be due to racial differences.

Purpose: The aim of this study was to investigate regional differences between morphologic and functional changes in the same patients with mild Alzheimer's disease (AD) using statistical parametric mapping (SPM) and voxel-based morphometry (VBM)., Methods: Thirty patients with very mild AD (mean age 66.8 years, mean MMSE score 24.0) and 30 age- and sex-matched normal volunteers underwent both( 18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and three-dimensional spoiled gradient echo (SPGR) magnetic resonance imaging (MRI). Statistical parametric mapping was used to conduct VBM analysis of the morphological data, which were compared voxel by voxel with the results of a similar analysis of the glucose metabolic data., Results: In AD patients, VBM data indicated a significant gray matter volume density decrease in bilateral amygdala/hippocampus complex (p < 0.05, corrected), while FDG-PET analysis showed significant glucose metabolic reductions in the posterior cingulate gyri and the right parietal lobule, compared with those in the normal control group., Conclusion: In very mild AD, morphological change occurs in the medial temporal lobes, while in contrast, metabolic changes occur in the posterior cingulate gyri and parietal lobule.

Background and Purpose: 2-[Fluorine 18]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) has played an important role in detecting hypometabolic regions in the brains of patients with dementia. To our knowledge, the optimal imaging time for dementia has not been investigated. The aim of this study was to evaluate the sensitivity of the early scanning (ES) compared with late scanning (LS) for demonstrating decreased regional glucose metabolism in patients with Alzheimer disease (AD)., Methods: Twenty patients with mild AD (mean age +/- standard deviation, 64.8 +/- 5.2 years) and 20 age- and sex-matched healthy volunteers (age, 65.9 +/- 4.5 years) were underwent FDG PET. Their cerebral glucose metabolic images were obtained on ES at 30-42 minutes and LS at 60-72 minutes after the administration of FDG 185-346 MBq. We compared regional cerebral metabolic images in a voxel-by-voxel analysis with statistical parametric mapping between patients with AD and control subjects and evaluated the difference in the hypometabolic regions between the two scans., Results: In the AD-to-healthy comparison, LS at the P < .001 level of significance showed more extensive and significant hypometabolic areas than did ES., Conclusion: These results indicate that LS is superior to ES in detecting hypometabolic regions in patients with AD. For patients with AD, emission scanning soon after the administration of FDG is probably not advised.

Background and Purpose: Voxel-based morphometry (VBM), used for detecting brain atrophy, permits comparison of local gray matter concentration at every voxel in an image between two groups. We sought to delineate the specific patterns of cerebral gray matter loss with regard to onset of Alzheimer's disease (AD) by using MR imaging and VBM and to evaluate the diagnostic performance of VBM with Z score images., Methods: Two groups of 30 patients with mild AD of different ages of onset were examined. Mean ages in the early- and late-onset groups were 60.2 +/- 5.2 and 71.5 +/- 2.6 years, respectively. Control subjects were aged-matched healthy volunteers. Regions of gray matter loss in early- and late-onset AD were examined with VBM. Diagnostic performance of Z score images obtained with the VBM method was evaluated in patients and control subjects by calculating the area under the receiver operating characteristic curve (A(z))., Results: Both AD groups had significantly reduced gray matter in the bilateral medial temporal regions. In addition, the early-onset group had more severe gray matter loss in the bilateral parietal and posterior cingulate cortices and precuneus region. No difference was noted in diagnostic performance of Z score images between the early- (A(z) = 0.9435) and late-onset (A(z) = 0.9018) groups., Conclusion: Differences were noted in the patterns of regional gray matter loss in patients with early-onset AD versus those with late-onset AD. Parietotemporal and posterior cingulate gray matter loss was found in early-onset AD but not in late-onset AD. Z score images obtained with VBM had a great diagnostic performance for mild AD and can be applied for detecting mild AD in clinical examinations.

By using [(18)F]-2-fluoro-deoxy-d-glucose and positron emission tomography, the authors studied changes in regional glucose metabolism after a 1-year interval in patients with mild Alzheimer's disease (AD). Glucose metabolism declined over time in the bilateral precuneus and posterior cingulate gyri and in the frontal, temporal, and parietal cortices. Glucose metabolism in these regions may be a useful measure of the progression of AD and a valid surrogate outcome measure of clinical drug trials.

Unlabelled: The purpose of this study was to delineate the specific patterns of cerebral glucose metabolism with regard to the time of onset of Alzheimer's disease (AD)., Methods: Two groups of 20 AD patients with different ages of onset were examined. The early onset (EO) and late onset (LO) groups had mean ages of onset of 53.9 and 72.7 years. Groups of age-matched normal subjects were used as controls. A regional relative cerebral glucose metabolic image of each subject was obtained by 2-[18F] fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET). NEUROSTAT program was used for spatial normalization and voxel-based statistical parametric mapping (SPM) 99 was used for statistical analyses., Results: Both AD groups had significant hypometabolic regions in the bilateral parieto-temporal regions compared with the age-matched groups. The EO group had more severe hypometabolism in the bilateral parietal and posterior cingulate cortices and precuneus region than the LO group. However, LO group showed no significant hypometabolic regions compared to the EO group., Conclusion: The effects of time of AD onset were delineated as a double dissociation, that is, EO AD patients have a more severe reduction of glucose metabolism. Our finding suggests the existence of biological subtypes of AD.