[Show abstract][Hide abstract] ABSTRACT: The neuropsychological features and neuropathological progression patterns associated with rapidly evolving cognitive decline or dementia in Parkinson's disease (PD) remain to be elucidated.
PLoS ONE 01/2014; 9(10):e110547. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Two methods are commonly used in brain image voxel-based analyses widely used for dementia work-ups: 3-dimensional stereotactic surface projections (3D-SSP) and statistical parametric mapping (SPM). The methods calculate the Z-scores of the cortical voxels that represent the significance of differences compared to a database of brain images with normal findings, and visualize them as surface brain maps. The methods are considered useful in amyloid positron emission tomography (PET) analyses to detect small amounts of amyloid-β deposits in early-stage Alzheimer's disease (AD), but are not fully validated. We analyzed the (11)C-labeled 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole (BF-227) amyloid PET imaging of 56 subjects (20 individuals with mild cognitive impairment [MCI], 19 AD patients, and 17 non-demented [ND] volunteers) with 3D-SSP and the easy Z-score imaging system (eZIS) that is an SPM-based method. To clarify these methods' limitations, we visually compared Z-score maps output from the two methods and investigated the causes of discrepancies between them. Discrepancies were found in 27 subjects (9 MCI, 13 AD, and 5 ND). Relatively high white matter uptake was considered to cause higher Z-scores on 3D-SSP in 4 subjects (1 MCI and 3 ND). Meanwhile, in 17 subjects (6 MCI, 9 AD, and 2 ND), Z-score overestimation on eZIS corresponded with high skull uptake and disappeared after removing the skull uptake ("scalping"). Our results suggest that non-specific uptakes in the white matter and skull account for errors in voxel-based amyloid PET analyses. Thus, diagnoses based on 3D-SSP data require checking white matter uptake, and "scalping" is recommended before eZIS analysis.
The Tohoku Journal of Experimental Medicine 01/2014; 234(3):175-81. · 1.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sarcoidosis or sarcoid reactions, which appear as FDG-avid lesions in oncologic patients, need to be differentiated from disseminated malignancies. We aimed to promote awareness of development of sarcoidosis or sarcoid reactions after antineoplastic therapy to avoid diagnostic errors with FDG-PET/CT findings and assess the utility of FDG-PET/CT for follow-up. We retrospectively reviewed radiological reports of FDG-PET/CT scans performed between January 2009 and December 2011. Among oncologic patients with more than 2 FDG-PET/CT scans, those with nearly symmetrical increases in FDG uptake in the hilar or mediastinal lymph nodes were identified, and those with known sarcoidosis, concurrent diagnoses of sarcoidosis with malignancy, or histopathologically proven malignancies were excluded. Then, only those cases were selected for which sarcoidosis or sarcoid reactions were diagnosed. Four of 376 oncologic cases met the criteria. At 9 months to 6 years after antineoplastic therapy, abnormal FDG uptakes were observed in the hilar, mediastinal, abdominal, pelvic, and inguinal nodes, and/or spleen and lung parenchyma with SUVmax up to 17.7. On the basis of these findings, 1 patient received anticancer chemotherapy because of tumor recurrence suspicion. A gradual decrease in FDG uptake was observed on subsequent PET/CT scans. Sarcoidosis or sarcoid reactions should be considered in differential diagnosis of oncologic patients who have developed FDG-avid lesions any time after antineoplastic therapy. FDG-PET/CT can be used for follow-up in nondiagnostic situations to detect decreases in FDG uptake due to presence of sarcoidal granulomas.
[Show abstract][Hide abstract] ABSTRACT: 2-Deoxy-2-(18)F-fluoro-d-mannose ((18)F-FDM) is an (18)F-labeled mannose derivative and a stereoisomer of (18)F-FDG. Our preliminary study demonstrated that (18)F-FDM accumulated in tumors to the same extent as (18)F-FDG, with less uptake in the brain and faster clearance from the blood. However, detailed studies on the uptake of (18)F-FDM in tumors have not been conducted. We undertook this study to establish a practical method of (18)F-FDM synthesis based on an (18)F-nucleophilic substitution (SN2) reaction and to advance the biologic characterization of (18)F-FDM for potential application as a tumor-imaging agent.
We synthesized 4,6-O-benzylidene-3-O-ethoxymethyl-1-O-methyl-2-O-trifluoromethanesulfonyl-β-d-glucopyranoside as a precursor for the nucleophilic synthesis of (18)F-FDM. The precursor was radiofluorinated with (18)F-KF/Kryptofix222, followed by removal of the protecting groups with an acid. (18)F-FDM was purified by preparative high-performance liquid chromatography and then subjected to in vitro evaluation regarding phosphorylation by hexokinase as well as uptake and metabolism in AH109A tumor cells. The in vivo properties of (18)F-FDM were examined in Donryu rats bearing AH109A tumor cells by biodistribution studies and imaging with a small-animal PET system.
We radiosynthesized (18)F-FDM in sufficient radiochemical yields (50%-68%) with excellent purities (97.6%-98.7%). (18)F-FDM was phosphorylated rapidly by hexokinase, resulting in 98% conversion into (18)F-FDG-6-phosphate within 30 min. Tumor cells showed significant uptake of (18)F-FDM with time in vitro, and uptake was dose-dependently inhibited by d-glucose. (18)F-FDM injected into tumor-bearing rats showed greater uptake in tumors (2.17 ± 0.32 percentage injected dose per gram [%ID/g]) than in the brain (1.42 ± 0.10 %ID/g) at 60 min after injection. PET studies also revealed the tumor uptake of (18)F-FDM (quasi-standardized uptake value, 2.83 ± 0.22) to be the same as that of (18)F-FDG (2.40 ± 0.30), but the brain uptake of (18)F-FDM (1.89 ± 0.13) was ≈30% lower than that of (18)F-FDG (2.63 ± 0.26).
We prepared (18)F-FDM with good radiochemical yield and purity by an SN2 reaction. We demonstrated that (18)F-FDM had adequate tumor cell uptake by a metabolic trapping mechanism and can afford high-contrast tumor images with less uptake in the brain, indicating that (18)F-FDM has almost the same potential as (18)F-FDG for PET tumor imaging, with better advantages with regard to the imaging of brain tumors.
Journal of Nuclear Medicine 07/2013; · 5.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: Cigarette smoking decreases brain regional gray matter volume and is related to chronic obstructive lung disease (COPD). COPD leads to decreased pulmonary function, which is represented by forced expiratory volume in one second percentage (FEV1.0 %); however, it is unclear if decreased pulmonary function is directly related to brain gray matter volume decline. Because there is a link between COPD and cognitive decline, revealing a direct relationship between pulmonary function and brain structure is important to better understand how pulmonary function affects brain structure and cognitive function. Therefore, the purpose of this study was to analyze whether there were significant correlations between FEV1.0 % and brain regional gray and white matter volumes using brain magnetic resonance (MR) image data from 109 community-dwelling healthy elderly individuals. METHODS: Brain MR images were processed with voxel-based morphometry using a custom template by applying diffeomorphic anatomical registration using the exponentiated lie algebra procedure. RESULTS: We found a significant positive correlation between the regional white matter volume of the cerebellum and FEV1.0 % after adjusting for age, sex, and intracranial volume. CONCLUSION: Our results suggest that elderly individuals who have a lower FEV1.0 % have decreased regional white matter volume in the cerebellum. Therefore, preventing decreased pulmonary function is important for cerebellar white matter volume in the healthy elderly population.
[Show abstract][Hide abstract] ABSTRACT: Dysphagia is one of the cardinal symptoms of Parkinson's disease (PD). It is closely related to the quality of life and longevity of PD patients. The aim of the study is to clarify the pathophysiological mechanisms responsible for dysphagia in PD.
A cross-sectional and longitudinal comparative study.
Tohoku University Hospital.
Eight patients with dysphagia, 15 patients without dysphagia and 10 normal control subjects.
The time needed for swallowing initiation and changes in brain glucose metabolism at baseline and after a 3-year follow-up period.
The time needed for swallowing initiation was significantly longer in the patients with dysphagia compared with the patients without dysphagia at baseline and after the 3-year follow-up period (p<0.05). The patients with dysphagia exhibited hypometabolism in the supplementary motor area (SMA) and the anterior cingulate cortex (ACC) compared with the 10 normal control subjects at baseline (uncorrected p<0.001). After the 3-year follow-up period, the number of brain areas showing hypometabolism increased, involving not only the SMA and the ACC but also the bilateral medial frontal lobes, middle cingulate cortex, thalamus and right superior, middle, inferior and orbital frontal gyri (uncorrected p<0.001). In contrast, the patients without dysphagia showed virtually no regional hypometabolism at baseline (uncorrected p<0.001) and only a small degree of hypometabolism in the SMA and ACC after the 3-year follow-up period (uncorrected p<0.001).
These results suggest that dysphagia in PD patients is mainly related to a difficulty in swallowing initiation that is based on a combination of poor movement planning due to SMA dysfunction and impaired cognitive processing due to ACC dysfunction.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate age-related changes in the topological organization of structural brain networks by applying a longitudinal design over 6 years. Structural brain networks were derived from measurements of regional gray matter volume and were constructed in age-specific groups from baseline and follow-up scans. The structural brain networks showed economical small-world properties, providing high global and local efficiency for parallel information processing at low connection costs. In the analysis of the global network properties, the local and global efficiency of the baseline scan were significantly lower compared to the follow-up scan. Moreover, the annual rate of change in local and global efficiency showed a positive and negative quadratic correlation with the baseline age, respectively; both curvilinear correlations peaked at approximately the age of 50. In the analysis of the regional nodal properties, significant negative correlations between the annual rate of change in nodal strength and the baseline age were found in the brain regions primarily involved in the visual and motor/control systems, whereas significant positive quadratic correlations were found in the brain regions predominately associated with the default-mode, attention, and memory systems. The results of the longitudinal study are consistent with the findings of our previous cross-sectional study: the structural brain networks develop into a fast distribution from young to middle age (approximately 50 years old) and eventually became a fast localization in the old age. Our findings elucidate the network topology of structural brain networks and its longitudinal changes, thus enhancing the understanding of the underlying physiology of normal aging in the human brain.
Frontiers in Human Neuroscience 01/2013; 7:113. · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Positron emission tomography (PET) with (18)F-fluorodeoxyglucose ((18)F-FDG), a glucose analog, is widely used throughout the world as an indispensable imaging modality for the management of cancer treatment. This article reviews the pioneering achievements of PET in oncology with a focus on the development of PET that occurred from 1980 through the early-1990s. (18)F-FDG was first applied for imaging of animal tumors in 1980 and for brain tumor imaging clinically in 1982. (18)F-FDG enabled to visualize liver metastasis as clear positive image that could not be obtained by conventional nuclear imaging. Subsequently, (18)F-FDG was used for imaging various cancers, such as lung, pancreas, colorectal and hepatoma. (11)C-L-methionine ((11)C-MET) that reflects amino acid transport of cancers has an advantage that its uptake is lower in the brain and inflammatory tissue compared to (18)F-FDG, and was first applied for imaging lung cancer and brain tumor. (18)F-FDG and (11)C-MET were proved to be sensitive tracers that can be used to objectively evaluate the effectiveness of cancer treatment. The diagnostic accuracy of PET, which is critical in clinical practice, was evaluated for the differential diagnosis of malignant and benign lung nodules using (18)F-FDG or (11)C-MET. In addition to (18)F-FDG and (11)C-MET, many radiopharmaceuticals were developed, such as (18)F-labled thymidine analogs for evaluating proliferative activity, (18)F-fluoromisonidazole for imaging of hypoxia, and (18)F-fluorodeoxygalactose for evaluating liver-specific galactose metabolism and for imaging of hepatoma that retains galactose metabolic activity. These early efforts and achievements have greatly contributed to the development and clinical application of (18)F-FDG PET in oncology.
The Tohoku Journal of Experimental Medicine 01/2013; 230(3):155-69. · 1.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent studies have demonstrated developmental changes of functional brain networks derived from functional connectivity using graph theoretical analysis, which has been rapidly translated to studies of brain network organization. However, little is known about sex- and IQ-related differences in the topological organization of functional brain networks during development. In this study, resting-state fMRI (rs-fMRI) was used to map the functional brain networks in 51 healthy children. We then investigated the effects of age, sex, and IQ on economic small-world properties and regional nodal properties of the functional brain networks. At a global level of whole networks, we found significant age-related increases in the small-worldness and local efficiency, significant higher values of the global efficiency in boys compared with girls, and no significant IQ-related difference. Age-related increases in the regional nodal properties were found predominately in the frontal brain regions, whereas the parietal, temporal, and occipital brain regions showed age-related decreases. Significant sex-related differences in the regional nodal properties were found in various brain regions, primarily related to the default mode, language, and vision systems. Positive correlations between IQ and the regional nodal properties were found in several brain regions related to the attention system, whereas negative correlations were found in various brain regions primarily involved in the default mode, emotion, and language systems. Together, our findings of the network topology of the functional brain networks in healthy children and its relationship with age, sex, and IQ bring new insights into the understanding of brain maturation and cognitive development during childhood and adolescence.
PLoS ONE 01/2013; 8(2):e55347. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: The aim of this study was to survey the 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) cancer screening program conducted in Japan. METHODS: The "FDG-PET cancer screening program" included both FDG-PET and positron emission tomography with computed tomography (PET/CT) with or without other combined screening tests that were performed for cancer screening in asymptomatic subjects. A total of 155,456 subjects who underwent the FDG-PET cancer screening program during 2006-2009 were analyzed. RESULTS: Of the 155,456 subjects, positive findings suggesting possible cancer were noted in 16,955 (10.9 %). The number of cases with detected cancer was 1,912 (1.23 % of the total screened cases, annual range 1.14-1.30 %). Of the 1,912 cases of detected cancer, positive findings on FDG-PET were present in 1,491 cases (0.96 % of the total number of screened cases). According to the results of further examinations, the true positive rate for subjects with suggested possible cancer (positive predictive value) was 32.3 % with FDG-PET. Cancers of the colon/rectum, thyroid, lung, and breast were most frequently found (396, 353, 319, and 163 cases, respectively) with high PET sensitivity (85.9, 90.7, 86.8, 84.0 %, respectively). Prostate cancer and gastric cancer (165 and 124 cases, respectively) had low PET sensitivity (37.0 and 37.9 %, respectively). The Union for International Cancer Control (UICC) clinical stage of cancer found with the FDG-PET cancer screening program was mainly Stage I. CONCLUSIONS: The FDG-PET screening program in Japan has detected a variety of cancers at an early stage. However, several cancers were found in repeated FDG-PET cancer screening program, indicating the limitation of a one-time FDG-PET cancer screening program. The value of the FDG-PET cancer screening program is left to the judgment of individuals with regard to its potentials and limitations.
Annals of Nuclear Medicine 10/2012; · 1.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Orally administered I-labeled 15-(4-iodophenyl)-3(R,S)-methylpentadecanoic acid (BMIPP), a fatty acid analog, is absorbed from the intestine and ascends to the venous angle through the thoracic duct (TD). The objective of this study was to evaluate the clinical feasibility of 3-dimensional (3D) TD scintigraphy using SPECT/CT and BMIPP for the detection of anatomical anomalies of TD.
This study included 35 consecutive patients with esophageal cancer who underwent tumor resection after TD scintigraphy. For scintigraphy, 111 MBq of BMIPP was orally administered, and static images and SPECT/CT images were obtained. On the basis of the SPECT/CT fusion images, TD was divided into the following 4 segments: cervical, upper thoracic, middle thoracic, and lower thoracic. The TD visualization was categorized into 5 grades, from grade 1 (poor) to 5 (excellent). In addition, the diagnostic accuracy of 3D TD scintigraphy for the detection of anatomical anomalies of TD was calculated using the intraoperative finding as a criterion standard.
The TD visualization grades for the cervical, upper, middle, and lower thoracic segments were 4.4 ± 0.6, 3.7 ± 1.0, 3.1 ± 0.8, and 2.1 ± 0.9, respectively. The TD scintigraphy demonstrated an uncommon accumulation including that in the right- or bilateral-sided mediastinum or venous angle in 6 (17%) of the 35 patients. Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of 3D TD scintigraphy for the detection of anatomical anomalies of TD were 0.75, 0.90, 0.5, 0.97, and 0.89, respectively.
Three-dimensional TD scintigraphy by BMIPP is a simple and minimally invasive method for imaging the anatomical configuration of the TD and for detecting any anatomical anomalies, except in the lower thoracic segment.
Clinical nuclear medicine 09/2012; 37(11):1047-51. · 3.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Prader-Willi syndrome (PWS) is a genetically determined neurodevelopmental disorder and is generally regarded as a genetic model of obesity. Individuals with PWS exhibit behavioral symptoms including temper tantrums, rigid thinking, and compulsive behavior. The most striking feature of PWS is abnormal eating behavior, including hyperphagia, intense preoccupation with food, and incessant food seeking. To explore brain regions associated with the behavioral symptoms of PWS, we investigated differences in resting-state regional cerebral blood flow (rCBF) between individuals with PWS and healthy controls. Correlation analyses were also performed to examine the relationship between rCBF and altered eating behavior in PWS individuals. Methods: Twelve adults with PWS and 13 age- and gender-matched controls underwent resting-state single photon emission computerized tomography (SPECT) with N-isopropyl-p-[(123)I] iodoamphetamine (IMP). The rCBF data were analyzed on a voxel-by-voxel basis using SPM5 software. Results: The results demonstrated that compared with controls, individuals with PWS had significantly lower rCBF in the right thalamus, left insular cortex, bilateral lingual gyrus, and bilateral cerebellum. They had significantly higher rCBF in the right inferior frontal gyrus, left middle/inferior frontal gyrus (anterior and posterior clusters), and bilateral angular gyrus. Additionally, rCBF in the left insula, which was significantly lower in PWS individuals, was negatively correlated with the eating behavior severity score. Conclusions: These results suggest that specific brain regions, particularly the left insula, may be partly responsible for the behavioral symptoms in PWS.
[Show abstract][Hide abstract] ABSTRACT: The Clinical Dementia Rating (CDR) is an assessment of dementia severity based on observations of activities of daily living, and a CDR of 0.5 (CDR 0.5) represents questionable dementia. A combination of the Cognitive Abilities Screening Instrument (CASI) and the Trail Making Test (TMT) scores discriminated CDR 0.5 subjects from healthy participants with a high degree of accuracy. We investigated the neurological background of CDR 0.5 subjects by correlating CASI and TMT scores with regional cerebral blood flow (rCBF) as measured by single photon emission computed tomography (SPECT).
From a community-based cohort, 22 CDR 0.5 participants were recruited. CASI and TMT scores, rCBF measure using [(123) I]-N-isopropyl-p-iodoamphetamine and SPECT were obtained. We evaluated the relationships between the CASI domain scores, between TMT scores and rCBF in a regions-of-interest-based analysis, and voxel-based analysis using Statistical Parametric Mapping 5 software.
We found that lower rCBF in the left medial temporal cortex correlated with a decreased CASI domain recent memory score both in the regions-of-interest and statistical parametric mapping analysis. In both the regions-of-interest and statistical parametric mapping analysis, the rCBF in the left prefrontal cortex correlated with CASI domain remote memory and mental manipulation and concentration.
Our results indicate that some CDR 0.5 subjects have functional impairments in the medial temporal lobe as well as in the prefrontal cortex, as reflected in the cognitive decline measured by CASI and TMT.
[Show abstract][Hide abstract] ABSTRACT: Dementia is one of the most debilitating symptoms of Parkinson's disease. A recent longitudinal study suggests that up to 80% of patients with Parkinson's disease will eventually develop dementia. Despite its clinical importance, the development of dementia is still difficult to predict at early stages. We previously identified olfactory dysfunction as one of the most important indicators of cortical hypometabolism in Parkinson's disease. In this study, we investigated the possible associations between olfactory dysfunction and the risk of developing dementia within a 3-year observation period. Forty-four patients with Parkinson's disease without dementia underwent the odour stick identification test for Japanese, memory and visuoperceptual assessments, (18)F-fluorodeoxyglucose positron emission tomography scans and magnetic resonance imaging scans at baseline and 3 years later. A subgroup of patients with Parkinson's disease who exhibited severe hyposmia at baseline showed more pronounced cognitive decline at the follow-up survey. By the end of the study, 10 of 44 patients with Parkinson's disease had developed dementia, all of whom had severe hyposmia at baseline. The multivariate logistic analysis identified severe hyposmia and visuoperceptual impairment as independent risk factors for subsequent dementia within 3 years. The patients with severe hyposmia had an 18.7-fold increase in their risk of dementia for each 1 SD (2.8) decrease in the score of odour stick identification test for Japanese. We also found an association between severe hyposmia and a characteristic distribution of cerebral metabolic decline, which was identical to that of dementia associated with Parkinson's disease. Furthermore, volumetric magnetic resonance imaging analyses demonstrated close relationships between olfactory dysfunction and the atrophy of focal brain structures, including the amygdala and other limbic structures. Together, our findings suggest that brain regions related to olfactory function are closely associated with cognitive decline and that severe hyposmia is a prominent clinical feature that predicts the subsequent development of Parkinson's disease dementia.