Jun Takeuchi

Design, synthesis, and uniquely electron-spin-polarized quartet photo-excited state of a π-conjugated spin system generated via the ion-pair state

A functionalized verdazyl radical, 1, was synthesized, which consists of a bodipy acceptor (A), a phenyl-anthracene donor (D), and a stable verdazyl radical (R). Optical measurements, electron spin resonance (ESR), time-resolved ESR (TRESR), and laser-excitation pulsed ESR experiments were carried out. The efficient intra-molecular energy transfer (EnT) from the anthracene moiety to the bodipy functional component was observed by time-resolved fluorescence spectroscopy and TRESR measurements. A unique dynamic electron-spin polarization (DEP) was detected for the quartet photo-excited state of 1 by TRESR and pulsed ESR. Such a unique DEP was not detected for either the parent verdazyl radical2 without the bodipy acceptor or new compound 3 with an anthraquinone moiety instead of the bodipy component. The spectral simulation of the quartet spectrum of 1 revealed that the unique DEP was generated by competition between a mechanism involving the intra-molecular ion pair *A−–D+–R and spin–orbit intersystem crossing. The dynamic electron-spin polarization via the ion-pair state and the mechanism were discussed based on the experimental data and theoretical calculations. The electronic structure and the spin delocalization in the photo-excited quartet state of 1 were discussed by comparison with the results of 3.

Clinical Features of Pittsburgh Compound-B-Negative Dementia

Background/Aims: We previously found that some cases of clinically diagnosed Alzheimer’s disease (AD) were rated as Pittsburgh compound B (PiB) negative by amyloid imaging (i.e. cases of PiB-negative dementia). The present study was designed to analyze the clinical features of PiB-negative dementia patients in detail. Methods: Of the 64 cases of clinically diagnosed AD, 14 were rated PiB negative. Eleven of these were further analyzed using CSF biomarker levels and findings from MRI, FDG-PET, 123I-MIBG myocardial scintigraphy and voxel-based morphometry (VBM). Results: When examined by 123I-MIBG myocardial scintigraphy, the heart/mediastinum ratio was significantly higher in the PiB-negative dementia group than in the dementia with Lewy bodies (DLB) group. Analyses of CSF biomarkers and MRI and FDG-PET findings suggested argyrophilic grain disease (AGD) in 3 cases, frontotemporal lobar degeneration (FTLD) in 3 cases, neurofibrillary tangle-predominant dementia (NFTD) in 1 case, and AD in 2 cases. In the VBM data analysis, the PiB-positive AD group showed significant atrophy of both hippocampi compared with the healthy control group, while the PiB-negative dementia group presented with significant atrophy of the left precuneus. Conclusion: PiB-negative dementia is unlikely to include DLB, while it most likely includes diseases of tauopathy, such as FTLD, AGD and NFTD. A better understanding of PiB-negative dementia is expected to further improve the accuracy of the clinical AD diagnosis.

Cerebral blood flow abnormality in clinically diagnosed Alzheimer's disease patients with or without amyloid β accumulation on positron emission tomography

The detection of amyloid β accumulation might be useful in confirming the diagnosis of Alzheimers disease in clinically suspected cases. However, confirmation of the disease by a positron emission tomography scan is not always available.

A case of neurosarcoidosis with recurrent brainstem infarction, obstructive hydrocephalus and brainstem atrophy

We report the case of a 42-year-old female with neurosarcoidosis who was hospitalized in year 2017 for gait disturbance. In 2011, she suddenly had vertigo that lasted for a few days. In 2013, she noticed left hemiplegia. A brain MRI revealed an acute infarction on the right side of the upper pons extending longitudinally from the ventral surface. In 2017, she again had left lower limb paralysis. A Brain MRI showed another infarction on the right side of the mid-pons. Hydrocephalus and brainstem atrophy were also noted. The patient was referred to our hospital. Upon neurological examination, she presented with down beat nystagmus, muscle weakness on the left side, and a broad-based spastic gait. CSF findings included an increased number of cells and protein levels with decreased glucose levels. A contrast-enhanced MRI revealed basilar meningitis causing hydrocephalus. A contrast CT scan revealed inguinal lymph node swelling, and scintigram found gallium accumulation. We diagnosed sarcoidosis via a lymph node biopsy. We speculate that chronic basilar meningitis obstructed the patients branching penetrating arteries inducing infarction together with obstruction of the spinal fluid flow causing hydrocephalus and cerebral atrophy.

Amyloid deposition and CBF patterns predict conversion of mild cognitive impairment to dementia

Mild cognitive impairment (MCI) can include the transition from a normal state to dementia. To explore biomarkers for the development of dementia, we performed an 18-month follow-up study in 28 patients with amnestic MCI. Amyloid deposition was examined using PiB PET, and cerebral blood flow (CBF) was examined using SPECT. Cognitive function was periodically assessed. The rate of conversion to dementia was higher in the PiB-positive/equivocal group (74%) than in the PiB-negative group (33%) (p = 0.041). Perfusion SPECT was performed in 16 patients. MCI patients with an AD-characteristic pattern of reduced CBF had a higher PiB-positive/equivocal rate (82%) than those with a non-AD pattern (20%) (p = 0.018), and patients with an AD pattern had a higher conversion rate (82%) than those with a non-AD pattern (40%) (p = 0.094). Clinically, all PiB-positive converters were diagnosed as having Alzheimer’s disease (AD), whereas PiB-negative converters were thought to have some form of dementia other than AD. Amyloid PET is useful for predicting conversion to AD in MCI patients. A pattern analysis of perfusion SPECT findings might also be helpful for predicting conversion to AD, but with a lower specificity.

AMYLOID AND TAU IMAGING IN PATIENTS WITH POSTERIOR CORTICAL ATROPHY

P2-361 AMYLOID AND TAU IMAGING IN PATIENTS WITH POSTERIOR CORTICAL ATROPHY Akitoshi Takeda, Jun Takeuchi, Haruna Saito, Joji Kawabe, Yasuhiro Wada, Aya Mawatari, Hisashi Doi, Yasuyoshi Watanabe, Soichiro Kitamura, Hitoshi Shimada, Makoto Higuchi, Tetsuya Suhara, Yoshiaki Itoh, Osaka City University, Osaka, Japan; RIKEN Center for Life Science Technologies, Kobe, Japan; National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan. Contact e-mail: a-taked@ med.osaka-cu.ac.jp

Localized Accumulation of Tau without Amyloid-Beta in Aged Brains Measured with [11C]PBB3 and [11C]Pib Positron Emission Tomography

Objective: Different regional specificity in tau accumulation is well known in Alzheimer’s disease (AD) brains. However, little is known about such distribution in aging brains and mild cognitive impairment (MCI) brains. Methods: Cognitive functions and regional accumulation of tau and amyloid β (Aβ) were evaluated in 13 healthy controls (HCs), 3 patients with MCI and 4 AD patients. Tau and Aβ accumulation was semi-quantitatively measured with positron emission tomography (PET) using [11C]pyridinyl-butadienyl-benzothiazole 3 (PBB3) and [11C]Pittsburgh compound-B (PiB). Results: Age-dependent accumulation of tau was found in all predetermined regions characteristic of AD, especially in the parahippocampal gyrus, lateral temporal cortex, frontal cortex, and posterior cingulate gyrus, where age-dependency was statistically significant. In contrast, age-dependency in accumulation of Aβ was not observed in most regions assessed in HC. Moreover, the accumulation of tau in regions characteristic of AD in MCI patients was higher than that in HC, whereas tau accumulation was highest and statistically significant in AD patients. Unlike HC, the accumulation of tau was accompanied by that of Aβ in patients with MCI and AD. Conclusion: Mild and age-dependent accumulation of tau without Aβ was found in AD-related areas in aging brains. Considering age as a major risk for AD, higher accumulation of tau may trigger the neurodegenerative process of AD.

A Male Case with ò-Propeller Protein-Associated Neurodegeneration(BPAN) with Somatic Mosaic Mutation in WDR45

A 44 year old male presented with gait disturbance and showed rigidity, bradykinesia and small steppage gait. In his infancy, he had mental and motor retardation. MRI revealed pathognomonic iron deposition. He was diagnosed to have β-propeller protein-associated neurodegeneration (BPAN) with a de novo somatic mosaic mutation in WDR45.

Clinical features of Pittsburgh compound-B–negative dementia

BACKGROUND/AIMS We previously found that some cases of clinically diagnosed Alzheimers disease (AD) were rated as Pittsburgh compound B (PiB) negative by amyloid imaging (i.e. cases of PiB-negative dementia). The present study was designed to analyze the clinical features of PiB-negative dementia patients in detail. METHODS Of the 64 cases of clinically diagnosed AD, 14 were rated PiB negative. Eleven of these were further analyzed using CSF biomarker levels and findings from MRI, FDG-PET, (123)I-MIBG myocardial scintigraphy and voxel-based morphometry (VBM). RESULTS When examined by (123)I-MIBG myocardial scintigraphy, the heart/mediastinum ratio was significantly higher in the PiB-negative dementia group than in the dementia with Lewy bodies (DLB) group. Analyses of CSF biomarkers and MRI and FDG-PET findings suggested argyrophilic grain disease (AGD) in 3 cases, frontotemporal lobar degeneration (FTLD) in 3 cases, neurofibrillary tangle-predominant dementia (NFTD) in 1 case, and AD in 2 cases. In the VBM data analysis, the PiB-positive AD group showed significant atrophy of both hippocampi compared with the healthy control group, while the PiB-negative dementia group presented with significant atrophy of the left precuneus. CONCLUSION PiB-negative dementia is unlikely to include DLB, while it most likely includes diseases of tauopathy, such as FTLD, AGD and NFTD. A better understanding of PiB-negative dementia is expected to further improve the accuracy of the clinical AD diagnosis.

PiB negative dementia: Pitfall of clinical diagnosis of Alzheimer's disease

Background: The relative utility of the positron emission tomography (PET) radioligand N-methyl-11C-2-(4-methylaminophenyl)-6-hydroxybenzothiazole (also known as 11C-6-OH-BTA-1 or 11C-PIB) and 18F-fluorodeoxyglucose (18F-FDG) in distinguishing Alzheimer’s Disease (AD), mild cognitive impairment (MCI) and controls (CTR) is not fully established. Methods: Patients with mild AD (n 1⁄4 18), MCI (n 1⁄4 24) and CTR subjects (n 1⁄4 18) were studied. A diagnostic evaluation, neuropsychological tests, 11C-PIB PET, 18F-FDG PET, and structural MRI were done. For 11C-PIB, region of interest (ROI) binding potentials (BPND) from the Logan graphical method were obtained, using cerebellar reference. For 18F-FDG, regional cerebral metabolic rate for glucose (rCMRGlu) was obtained using an arterial input function. Results: The three subject groups (n 1⁄4 59) differed in 11C-PIB BPND in prefrontal cortex (p < .001), cingulate (p < .001), parietal cortex (p < .001), precuneus (p < .001) and parahippocampal gyrus (p < .004), but not hippocampus. These differences occurred in the AD-CTR and AD-MCI comparisons, with no significant differences between MCI and CTR. For 18F-FDG (n 1⁄4 51), rCMRGlu differed across the three groups in the precuneus (p 1⁄4 0.004) and parietal cortex (p 1⁄4 0.02). These differences occurred in the AD-CTR and AD-MCI comparisons, with no significant differences between MCI and CTR. Mean 11C-PIB BPND was higher in AD compared to CTR, and MCI compared to CTR. Mean 18F-FDG rCMRGlu did not differ among the groups. 11C-PIB BPND showed strong inverse correlations with cognitive test scores in prefrontal, cingulate, parietal and precuneus, but not hippocampus. 18F-FDG rCMRGlu showed less robust positive correlations with cognitive test scores, primarily in parietal cortex and precuneus. For each ROI, when both 11C-PIB BPND and 18F-FDG rCMRGlu were entered into logistic regression models, 11C-PIB BPND significantly differed between AD and CTR in prefrontal, cingulate, parietal and parahippocampal gyrus, and between AD and MCI in prefrontal, cingulate, parietal and precuneus. 18F-FDG rCMRGlu was not significant in these analyses. Conclusions: When evaluated simultaneously, 11C-PIB BPND but not 18F-FDG rCMRGlu had group discriminating ability. The ability of 11C-PIB PET to distinguish AD, MCI and CTR underlines its potential use in differential diagnosis, and patient selection and monitoring in treatment trials.