Yutaka Arahata

Discrimination between Alzheimer Dementia and Controls by Automated Analysis of Multicenter FDG PET

A new diagnostic indicator of FDG PET scan abnormality, based on age-adjusted t statistics and an automated voxel-based procedure, is presented and validated in a large data set comprising 110 normal controls and 395 patients with probable Alzheimers disease (AD) that were studied in eight participating centers. The effect of differences in spatial resolution of PET scanners was minimized effectively by filtering and masking. In controls FDG uptake declined significantly with age in anterior cingulate and frontolateral perisylvian cortex. In patients with probable AD decline of FDG uptake in posterior cingulate, temporoparietal, and prefrontal association cortex was related to dementia severity. These effects were clearly distinct from age effects in controls, suggesting that the disease process of AD is not related to normal aging. Women with probable AD had significantly more frontal metabolic impairment than men. The new indicator of metabolic abnormality in AD-related regions provided 93% sensitivity and specificity for distinction of mild to moderate probable AD from normals, and 84% sensitivity at 93% specificity for detection of very mild probable AD (defined by Mini Mental Score 24 or better). All regions related to AD severity were already affected in very mild AD, suggesting that all vulnerable areas are affected to a similar degree already at disease onset. Ventromedial frontal cortex was also abnormal. In conclusion, automated analysis of multicenter FDG PET is feasible, provides insights into AD pathophysiology, and can be used potentially as a sensitive biomarker for early AD diagnosis.

Occipital hypoperfusion in Parkinson’s disease without dementia: correlation to impaired cortical visual processing

Objective: The purpose of this study was to analyse changes in regional cerebral blood flow (rCBF) in Parkinson’s disease (PD) without dementia. Methods: Twenty eight non-demented patients with PD and 17 age matched normal subjects underwent single photon emission computed tomography with N-isopropyl-p-[123I]iodoamphetamine to measure rCBF. The statistical parametric mapping 96 programme was used for statistical analysis. Results: The PD patients showed significantly reduced rCBF in the bilateral occipital and posterior parietal cortices (p<0.01, corrected for multiple comparison p<0.05), when compared with the control subjects. There was a strong positive correlation between the score of Raven’s coloured progressive matrices (RCPM) and the rCBF in the right visual association area (p<0.01, corrected for multiple comparison p<0.05) among the PD patients. Conclusions: This study showed occipital and posterior parietal hypoperfusion in PD patients without dementia. Furthermore, it was demonstrated that occipital hypoperfusion is likely to underlie impairment of visual cognition according to the RCPM test, which is not related to motor impairment.

Visual hallucination in Parkinson's disease with FDG PET

To determine the characteristics of cerebral glucose metabolism in Parkinsons disease patients with visual hallucinations, group comparison studies using [18F]fluorodeoxyglucose positron emission tomography were performed. Nondemented Parkinsons disease patients in advanced stages were classified into two groups: (1) patients without visual hallucinations; (2) patients with visual hallucinations. Compared to patients without hallucinations, the relative regional cerebral glucose metabolic rate was greater in the frontal areas in patients with visual hallucinations, and the increase reached a significant level in the left superior frontal gyrus. Relative frontal hypermetabolism may be a feature of Parkinsons disease patients with visual hallucinations.

Cortical hypometabolism and hypoperfusion in Parkinson's disease is extensive: Probably even at early disease stages

Recent cerebral blood flow (CBF) and glucose consumption (CMRglc) studies of Parkinson’s disease (PD) revealed conflicting results. Using simulated data, we previously demonstrated that the often-reported subcortical hypermetabolism in PD could be explained as an artifact of biased global mean (GM) normalization, and that low-magnitude, extensive cortical hypometabolism is best detected by alternative data-driven normalization methods. Thus, we hypothesized that PD is characterized by extensive cortical hypometabolism but no concurrent widespread subcortical hypermetabolism and tested it on three independent samples of PD patients. We compared SPECT CBF images of 32 early-stage and 33 late-stage PD patients with that of 60 matched controls. We also compared PET FDG images from 23 late-stage PD patients with that of 13 controls. Three different normalization methods were compared: (1) GM normalization, (2) cerebellum normalization, (3) reference cluster normalization (Yakushev et al.). We employed standard voxel-based statistics (fMRIstat) and principal component analysis (SSM). Additionally, we performed a meta-analysis of all quantitative CBF and CMRglc studies in the literature to investigate whether the global mean (GM) values in PD are decreased. Voxel-based analysis with GM normalization and the SSM method performed similarly, i.e., both detected decreases in small cortical clusters and concomitant increases in extensive subcortical regions. Cerebellum normalization revealed more widespread cortical decreases but no subcortical increase. In all comparisons, the Yakushev method detected nearly identical patterns of very extensive cortical hypometabolism. Lastly, the meta-analyses demonstrated that global CBF and CMRglc values are decreased in PD. Based on the results, we conclude that PD most likely has widespread cortical hypometabolism, even at early disease stages. In contrast, extensive subcortical hypermetabolism is probably not a feature of PD.

High performance plasma amyloid-β biomarkers for Alzheimer’s disease

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 Aβ1–40/Aβ1–42 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 11C-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 Aβ1–42 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.

Direct comparison study between FDG-PET and IMP-SPECT for diagnosing Alzheimer's disease using 3D-SSP analysis in the same patients

PurposeThe purpose of this study was to evaluate and compare the diagnostic ability of 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) and N-isopropyl-p-123I iodoamphetamine single photon emission computed tomography (IMP-SPECT) using three-dimensional stereotactic surface projections (3D-SSP) in patients with moderate Alzheimers disease (AD).Materials and methodsFDG-PET and IMP-SPECT were performed within 3 months in 14 patients with probable moderate AD. Z-score maps of FDG-PET and IMP-SPECT images of a patient were obtained by comparison with data obtained from control subjects. Four expert physicians evaluated and graded the glucose hypometabolism and regional cerebral blood flow (rCBF), focusing in particular on the posterior cingulate gyri/precunei and parietotemporal regions, and determined the reliability for AD. Receiver operating characteristic (ROC) curves were applied to the results for clarification. To evaluate the correlation between two modalities, the regions of interest (ROIs) were set in the posterior cingulate gyri/precunei and parietotemporal region on 3D-SSP images, and mean Z-values were calculated.ConclusionNo significant difference was observed in the area under the ROC curve (AUC) between FDG-PET and IMP-SPECT images (FDG-PET 0.95, IMP-SPECT 0.94). However, a significant difference (P < 0.05) was observed in the AUC for the posterior cingulate gyri/precuneus (FDG-PET 0.94, IMP-SPECT 0.81). The sensitivity and specificity of each modality were 86%, and 97% for FDG-PET and 70% and 100% for IMP-SPECT. We could find no significant difference between FDG-PET and IMP-SPECT in terms of diagnosing moderate AD using 3D-SSP. There was a high correlation between the two modalities in the parietotemporal region (Spearmans r = 0.82, P < 0.001). The correlation in the posterior cingulate gyri/precunei region was lower than that in the parietotemporal region (Spearmans r = 0.63, P < 0.016).

Parieto-occipital glucose hypometabolism in Parkinson's disease with autonomic failure

To investigate the characteristics of regional cerebral metabolism in a subgroup of patients with Parkinsons disease and autonomic failure, we studied seven patients with Parkinsons disease with autonomic failure (PA group), 11 patients with Parkinsons disease without apparent autonomic failure (PD group), and nine normal controls using fluoro-deoxyglucose positron emission tomography (FDG-PET). To determine differences in metabolic distribution among these groups, regional relative glucose metabolic rates (RGMR), which were normalized with cerebellar values, were calculated and age-adjusted covariance analyses were done. When compared with that of controls. RGMR in the cerebral cortex of the PA group was markedly reduced in the occipital cortex (P<0.001), inferior parietal cortex (P<0.005) and superior parietal cortex (P<0.005), but without a decrease in the sensory motor and medial temporal cortices, putamen and thalamus. In contrast, the PD group did not show significant focal hypometabolic distribution. Our findings raise the possibility that Parkinsons disease with autonomic failure may overlap with the features of dementia with Lewy bodies.

Extrastriatal Mean Regional Uptake of Fluorine-18-FDOPA in the Normal Aged Brain—An Approach Using MRI-Aided Spatial Normalization

The aim of this study was to define the mean regional 6-[(18)F]fluoro-l-dopa (FDOPA) uptake rate constant (K(i)) values in the striatal and extrastriatal regions of the brain of normal subjects using magnetic resonance imaging (MRI)-aided spatial normalization of the FDOPA K(i) image and using automatic region of interest (ROI) analysis. Dynamic three-dimensional FDOPA positron emission tomography (PET) and three-dimensional magnetic resonance (MR) images were acquired in 13 aged normal subjects. The FDOPA add image and the K(i) image of each subject were transformed into standard stereotactic space with the aid of individual coregistered MR image. The mean regional K(i) values of the striatal and extrastriatal regions before normalization were compared with the respective values after normalization. Then automatic ROI analysis was performed on the MRI-aided spatially normalized K(i) images of the 13 normal subjects. The K(i) values on original images and those on spatially normalized images were in good agreement, indicating that the spatial normalization technique did not change the regional K(i) values appreciably. Automatic ROI analysis of the spatially normalized FDOPA K(i) images of the normal subjects, showed high K(i) values in ventral and dorsal regions of the midbrain, amygdala, hippocampus, and medial prefrontal cortex, in addition to caudate nucleus and putamen, which correspond to the dopaminergic projections in the brain. Spatial normalization technique helped to establish a database of FDOPA K(i) images of normal subjects and high K(i) values were observed widely besides striatal regions corresponding to the dopaminergic projections in the brain.

Prediction of Outcomes in Mild Cognitive Impairment by Using 18F-FDG-PET: A Multicenter Study

BACKGROUND 18F-FDG-PET is defined as a biomarker of neuronal injury according to the revised National Institute on Aging–Alzheimer’s Association criteria. OBJECTIVE The objective of this multicenter prospective cohort study was to examine the value of 18F-FDG-PET in predicting the development of Alzheimer’s disease (AD) in patients with mild cognitive impairment (MCI). METHODS In total, 114 patients with MCI at 9 participating institutions underwent clinical and neuropsychological examinations, MRI, and 18F-FDG-PET at baseline. The cases were visually classified into predefined dementia patterns by three experts. Anautomated analysis for 18F-FDG-PET was also performed to calculate the PET score. Subjects were followed periodically for 3 years, and progression to dementia was evaluated. RESULTS In 47% of the patients with MCI, progression of symptoms justified the clinical diagnosis of “probable AD”. The PET visual interpretation predicted conversion to AD during 3-year follow-up with an overall diagnostic accuracy of 68%. Overall diagnostic accuracy of the PET score was better than that of PET visual interpretation at all follow-up intervals, and the optimized PET score threshold revealed the best performance at the 2-year follow-up interval with an overall diagnostic accuracy of 83%,a sensitivity of 70%, and a specificity of 90%. Multivariate logistic regression analysis identified the PET score as the most significant predictive factor distinguishing AD converters from non-converters. CONCLUSION The PET score is the most statistically significant predictive factor for conversion from MCI to AD, and the diagnostic performance of the PET score is more promising for rapid converters over 2 years.

Neuroradiologic and clinical abnormalities in dementia of diffuse neurofibrillary tangles with calcification (Kosaka–Shibayama disease)

We describe a characteristic dementia patient diagnosed as diffuse neurofibrillary tangles with calcification (DNTC). Neuropsychologically, dementia, including a decline in memory retention and intelligence, and anomic aphasia were recognized. Imaging revealed circumscribed temporal dominant atrophy and calcification of the basal ganglia and cerebellum. SPECT and FDG-PET revealed a remarkable reduction of blood flow and metabolism in the temporal lobes; however, there is no reduction in the basal ganglia and cerebellum, and FDOPA-PET also disclosed no abnormalities. This suggests that calcification and neuronal degeneration occur independently in DNTC.