Publications by authors named "Nobuyuki Okamura"

166 Publications

Identification of Heterogeneous Subtypes of Mild Cognitive Impairment Using Cluster Analyses Based on PET Imaging of Tau and Astrogliosis.

Front Aging Neurosci 2020 26;12:615467. Epub 2021 Jan 26.

Department of Neurology, Gil Medical Center, Gachon University College of Medicine, Incheon, South Korea.

Mild cognitive impairment (MCI) is a condition with diverse causes and clinical outcomes that can be categorized into subtypes. [F]THK5351 has been known to detect reactive astrogliosis as well as tau which is accompanied by neurodegenerative changes. Here, we identified heterogeneous groups of MCI patients using THK retention patterns and a graph theory approach, allowing for the comparison of risk of progression to dementia in these MCI subgroups. Ninety-seven participants including 60 MCI patients and individuals with normal cognition (NC, = 37) were included and undertook 3T MRI, [F]THK5351 PET, and detailed neuropsychological tests. [F]Flutemetamol PET was also performed in 62 participants. We calculated similarities between MCI patients using their regional standardized uptake value ratio of THK retention in 75 ROIs, and clustered subjects with similar retention patterns using the Louvain method based on the modularity of the graph. The clusters of patients identified were compared with an age-matched control group using a general linear model. Dementia conversion was evaluated after a median follow-up duration of 34.6 months. MCI patients were categorized into four groups according to their THK retention patterns: (1) limbic type; (2) diffuse type; (3) sparse type; and (4) AD type (retention pattern as in AD). Subjects of the limbic type were characterized by older age, small hippocampal volumes, and reduced verbal memory and frontal/executive functions. Patients of the diffuse type had relatively large vascular burden, reduced memory capacity and some frontal/executive functions. Co-morbidity and mortality were more frequent in this subgroup. Subjects of the sparse type were younger and declined only in terms of visual memory and attention. No individuals in this subgroup converted to dementia. Patients in the AD type group exhibited the poorest cognitive function. They also had the smallest hippocampal volumes and the highest risk of progression to dementia (90.9%). Using cluster analyses with [F]THK5351 retention patterns, it is possible to identify clinically-distinct subgroups of MCI patients and those at greater risk of progression to dementia.
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http://dx.doi.org/10.3389/fnagi.2020.615467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874013PMC
January 2021

Synthesis and pharmacokinetic characterisation of a fluorine-18 labelled brain shuttle peptide fusion dimeric affibody.

Sci Rep 2021 Jan 28;11(1):2588. Epub 2021 Jan 28.

Department of Pharmacology, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Aoba-ku, Sendai, Miyagi, 9808575, Japan.

Brain positron emission tomography (PET) imaging with radiolabelled proteins is an emerging concept that potentially enables visualization of unique molecular targets in the brain. However, the pharmacokinetics and protein radiolabelling methods remain challenging. Here, we report the performance of an engineered, blood-brain barrier (BBB)-permeable affibody molecule that exhibits rapid clearance from the brain, which was radiolabelled using a unique fluorine-18 labelling method, a cell-free protein radiosynthesis (CFPRS) system. AS69, a small (14 kDa) dimeric affibody molecule that binds to the monomeric and oligomeric states of α-synuclein, was newly designed for brain delivery with an apolipoprotein E (ApoE)-derived brain shuttle peptide as AS69-ApoE (22 kDa). The radiolabelled products F-AS69 and F-AS69-ApoE were successfully synthesised using the CFPRS system. Notably, F-AS69-ApoE showed higher BBB permeability than F-AS69 in an ex vivo study at 10 and 30 min post injection and was partially cleared from the brain at 120 min post injection. These results suggest that small, a brain shuttle peptide-fused fluorine-18 labelled protein binders can potentially be utilised for brain molecular imaging.
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http://dx.doi.org/10.1038/s41598-021-82037-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844286PMC
January 2021

Synthesis and evaluation of 2-pyrrolopyridinylquinoline derivatives as selective tau PET tracers for the diagnosis of Alzheimer's disease.

Nucl Med Biol 2021 Feb 26;93:11-18. Epub 2020 Oct 26.

Cyclotron and Radioisotope Center (CYRIC), Tohoku University, Sendai 980-8578, Japan. Electronic address:

Introduction: [F]THK-5351 was originally developed as a positron emission tomography (PET) imaging tracer for the detection of accumulated tau proteins, the pathological hallmark of Alzheimer's disease (AD). However, clinical studies of [F]THK-5351 revealed the existence of off-target binding to monoamine oxidase-B (MAO-B). To overcome this off-target binding, in this work, we synthesized and evaluated 2-pyrrolopyridinylquinoline (PPQ) derivatives as selective tau PET imaging tracers.

Methods: The core structure of PPQ derivatives was synthesized mainly using the Buchwald-Hartwig amination coupling reaction. All derivatives were evaluated for binding affinity towards tau and MAO-B by in vitro competitive binding assay. Radiosynthesis of PPQ derivatives was performed by F-radiolabeling of their tosylate precursors with activated [F]KF/Kryptofix222 complex in dimethylsulfoxide by heating at 110 °C for 10 min. The biological properties of these [F]PPQ derivatives were characterized by in vitro autoradiography of postmortem AD brain sections and by assay of ex vivo biodistribution in mice.

Results: The PPQ derivatives were synthesized, with yields of 49-84%. In vitro competitive binding assay revealed that two novel PPQ derivatives-PPQ8 and PPQ9-demonstrated high binding affinity for tau (IC = 4.9 and 6.9 nM, respectively). The radiosynthesis of [F]PPQ8 and [F]PPQ9 yielded 1.4% and 50.1% isolated non-decay corrected radiochemical yield, respectively, with >99% radiochemical purity. The molar radioactivities of [F]PPQ8 and [F]PPQ9 were 16.9 and 64.8 GBq/μmol, respectively. The in vitro and ex vivo biological characterization of [F]PPQ8 and [F]PPQ9 revealed that these tracers were selective for tau in AD brain sections without off-target binding, and they furthermore demonstrated brain uptake in normal mice.

Conclusions: F-labeled PPQ derivatives improved binding affinity and selectivity for tau aggregates in AD. Further structural optimization to improve pharmacokinetics for potent tau PET imaging tracers is required.
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http://dx.doi.org/10.1016/j.nucmedbio.2020.10.002DOI Listing
February 2021

F-THK5351 PET imaging in patients with progressive supranuclear palsy: associations with core domains and diagnostic certainty.

Sci Rep 2020 11 10;10(1):19410. Epub 2020 Nov 10.

Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, No. 5, Fuxing St., Guishan, Taoyuan, Taiwan.

The associations of F-THK5351 tau positron emission tomography (PET) findings with core domains of progressive supranuclear palsy (PSP) and its diagnostic certainty have yet to be fully elucidated. The F-THK5351 PET patterns of 17 patients with PSP (68.9 ± 6.5 years; 8 women) were compared with those observed in 28 age-matched and sex-matched (66.2 ± 4.5 years, 18 women) control subjects (CS). Tracer accumulation-as reflected by standardized uptake value ratios (SUVRs) and z-scores-was correlated with core domains of PSP and different levels of diagnostic certainty. Compared with CS, patients with PSP showed an increased F-THK5351 uptake in the globus pallidus and red nucleus. Patients with PSP and oculomotor dysfunction had significantly higher SUVRs in the midbrain, red nucleus, and raphe nucleus than those without. In addition, cases who meet criteria for level 1 (highest) certainty in the postural instability domain showed significantly higher SUVRs in the frontal, parietal, precuneus, and sensory-motor cortex. Patients with probable PSP had significantly higher SUVR values than those with possible PSP in multiple cortical (i.e., frontal, parietal, temporal, anterior cingulate gyrus, precuneus, and sensory-motor gyrus) and subcortical (i.e., putamen, thalamus, and raphe nucleus) regions. Patterns of F-THK5351 uptake were correlated to core domains of PSP-including oculomotor dysfunction and postural instability. Moreover, the degree of diagnostic certainty for PSP was appreciably associated with F-THK5351 PET findings.
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http://dx.doi.org/10.1038/s41598-020-76339-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656245PMC
November 2020

Anthraquinone-containing compound in rhubarb prevents indole production via functional changes in gut microbiota.

J Nat Med 2021 Jan 19;75(1):116-128. Epub 2020 Oct 19.

Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, 1 Sanzo, Gakuen-cho, Fukuyama, Hiroshima, 729-0292, Japan.

Indole is produced from dietary tryptophan by tryptophanase in intestinal bacteria, such as Escherichia coli. In the liver, indole is converted into indoxyl sulfate, a uremic toxin and risk factor for chronic kidney disease (CKD). Probiotics and prebiotics are currently used for suppressing CKD, but there are no drugs that directly suppress indole production. In this study, we developed an optimized HPLC method for analyzing indole production and evaluated the effect of diets and rhubarb on indole production via the changes of gut microbiota. In high-carbohydrate and high-fat diet-fed mice, the indole production was significantly higher than in high-fiber diet-fed mice. We further used the high-carbohydrate diet-fed mice as a model for examining the effect of rhubarb on indole production. The 20% methanol-eluted fraction of aqueous rhubarb extract significantly suppressed indole production, and the eluate constituent rhein 8-O-β-D-glucopyranoside (RG) contributed to this effect in a concentration-dependent manner. The effect of RG depended on the anthraquinone core substructure, i.e., the aglycone moiety (rhein) of RG, which appeared to inhibit the tryptophanase function in gut microbiota. Thus, in addition to earlier reports that rhubarb is an effective CKD treatment, our study demonstrated that the anthraquinone moiety in rhubarb prevents uremic toxin production via functional changes in gut microbiota, which suppresses CKD progression.
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http://dx.doi.org/10.1007/s11418-020-01459-wDOI Listing
January 2021

Investigation of reactive astrogliosis effect on post-stroke cognitive impairment.

J Neuroinflammation 2020 Oct 17;17(1):308. Epub 2020 Oct 17.

Department of Nuclear Medicine and Molecular Imaging Center, Linkou Chang Gung Memorial Hospital, No. 5, Fuxing St., Guishan, Taoyuan, Taiwan.

Background: The aim of this study is to investigate the associations between post-stroke cognitive impairment (PSCI) severity and reactive astrogliosis (RA) extent on normalized F-THK-5351 positron-emission tomography (PET) imaging in amyloid-negative patients with first-ever stroke.

Methods: We prospectively enrolled 63 amyloid-negative patients with first-ever stroke. Neurocognitive evaluation, MRI, F-THK-5351, and F-florbetapir PET were performed around 3 months after stroke. The F-THK-5351 uptake intensity was normalized using a signal distribution template to obtain the Z-SUM scores as the RA extent in the whole brain and cerebral hemisphere ipsilateral to stroke lesion. We evaluated stroke volume, leukoaraiosis, and brain atrophy on MRI. We used a comprehensive neurocognitive battery to obtain composite cognitive scores, and defined PSCI as a general cognitive function score < - 1. We analyzed the influence of Z-SUM scores on PSCI severity after adjusting for demographic, vascular, and neurodegenerative variables.

Results: Twenty-five of 63 stroke patients had PSCI. Patients with PSCI had older age, lower education, and more severe cortical atrophy and total Z-SUM scores. Total Z-SUM scores were significantly associated with general cognitive and executive functions at multiple regression models. Path analyses showed that stroke can exert cognitive influence directly by stroke itself as well as indirectly through RA, including total and ipsilateral Z-SUM scores, in patients with either right or left hemisphere stroke.

Conclusion: The patterns and intensity of F-THK-5351 uptake in amyloid-negative patients with first-ever stroke were associated with PSCI manifestations, which suggests that RA presents a modulating effect in PSCI development.
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http://dx.doi.org/10.1186/s12974-020-01985-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568828PMC
October 2020

F-SMBT-1: A Selective and Reversible PET Tracer for Monoamine Oxidase-B Imaging.

J Nucl Med 2021 Feb 9;62(2):253-258. Epub 2020 Jul 9.

Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan.

Reactive astrocytes play a key role in the pathogenesis of various neurodegenerative diseases. Monoamine oxidase-B (MAO-B) is one of the promising targets for the imaging of astrogliosis in the human brain. A novel selective and reversible MAO-B tracer, ()-(2-methylpyrid-5-yl)-6-[(3-F-fluoro-2-hydroxy)propoxy]quinoline (F-SMBT-1), was successfully developed via lead optimization from the first-generation tau PET tracer F-THK-5351. SMBT-1 was radiolabeled with F using the corresponding precursor. The binding affinity of radiolabeled compounds to MAO-B was assessed using saturation and competitive binding assays. The binding selectivity of F-SMBT-1 to MAO-B was evaluated by autoradiography of frozen human brain tissues. The pharmacokinetics and metabolism were assessed in normal mice after intravenous administration of F-SMBT-1. A 14-d toxicity study after the intravenous administration of F-SMBT-1 was performed using rats and mice. In vitro binding assays demonstrated a high binding affinity of F-SMBT-1 to MAO-B (dissociation constant, 3.7 nM). In contrast, it showed low binding affinity to MAO-A and protein aggregates such as amyloid-β and tau fibrils. Autoradiographic analysis showed higher amounts of F-SMBT-1 binding in the Alzheimer disease brain sections than in the control brain sections. F-SMBT-1 binding was completely displaced with the reversible MAO-B inhibitor lazabemide, demonstrating the high selectivity of F-SMBT-1 for MAO-B. Furthermore, F-SMBT-1 showed a high uptake by brain, rapid washout, and no radiolabeled metabolites in the brain of normal mice. F-SMBT-1 showed no significant binding to various receptors, ion channels, or transporters, and no toxic effects related to its administration were observed in mice and rats. F-SMBT-1 is a promising and selective MAO-B PET tracer candidate, which would be useful for quantitative monitoring of astrogliosis in the human brain.
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http://dx.doi.org/10.2967/jnumed.120.244400DOI Listing
February 2021

[¹⁸F]THK5351 PET Imaging in Patients with Mild Cognitive Impairment.

J Clin Neurol 2020 Apr;16(2):202-214

Department of Neurology, Gachon University Gil Medical Center, Incheon, Korea.

Background And Purpose: Mild cognitive impairment (MCI) is a condition with diverse clinical outcomes and subgroups. Here we investigated the topographic distribution of tau in vivo using the positron emission tomography (PET) tracer [¹⁸F]THK5351 in MCI subgroups.

Methods: This study included 96 participants comprising 38 with amnestic MCI (aMCI), 21 with nonamnestic MCI (naMCI), and 37 with normal cognition (NC) who underwent 3.0-T MRI, [¹⁸F]THK5351 PET, and detailed neuropsychological tests. [¹⁸F]flutemetamol PET was also performed in 62 participants. The aMCI patients were further divided into three groups: 1) verbal-aMCI, only verbal memory impairment; 2) visual-aMCI, only visual memory impairment; and 3) both-aMCI, both visual and verbal memory impairment. Voxel-wise statistical analysis and region-of-interest -based analyses were performed to evaluate the retention of [¹⁸F]THK5351 in the MCI subgroups. Subgroup analysis of amyloid-positive and -negative MCI patients was also performed. Correlations between [¹⁸F]THK5351 retention and different neuropsychological tests were evaluated using statistical parametric mapping analyses.

Results: [¹⁸F]THK5351 retention in the lateral temporal, mesial temporal, parietal, frontal, posterior cingulate cortices and precuneus was significantly greater in aMCI patients than in NC subjects, whereas it did not differ significantly between naMCI and NC participants. [¹⁸F] THK5351 retention was greater in the both-aMCI group than in the verbal-aMCI and visualaMCI groups, and greater in amyloid-positive than amyloid-negative MCI patients. The cognitive function scores were significantly correlated with cortical [¹⁸F]THK5351 retention.

Conclusions: [¹⁸F]THK5351 PET might be useful for identifying distinct topographic patterns of [¹⁸F]THK5351 retention in subgroups of MCI patients who are at greater risk of the progression to Alzheimer's dementia.
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http://dx.doi.org/10.3988/jcn.2020.16.2.202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174126PMC
April 2020

Plasma pharmacokinetic and metabolism of [F]THK-5317 are dependent on sex.

Nucl Med Biol 2020 May - Jun;84-85:28-32. Epub 2020 Jan 13.

Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, 2444 Seibersdorf, Austria. Electronic address:

Introduction: Tau deposition is one of the hallmarks of Alzheimer's disease (AD) and can be visualized and quantified using [F]THK-5317 together with kinetic modeling. To determine the feasibility of this approach, we measured blood/plasma pharmacokinetics and radiotracer metabolism in female and male rats.

Methods: Female and male rats (n = 11-12) were cannulated via the femoral artery for continuous blood sampling. Blood sampling was performed at regular intervals after intravenous injection of [F]THK-5317. After collection of the last blood sample, animals were sacrificed, and organs were excised. Blood from minute 5, 20 and 60 was centrifuged to obtain plasma. Radiolabeled metabolites in plasma, brain, liver and urine were analyzed by radio-thin-layer chromatography (radio-TLC).

Results: Plasma pharmacokinetics and metabolism were significantly different between female and male rats. [F]THK-5317 plasma clearance was faster in female (0.66 ± 0.08 mL/h/kg BW) than in male (0.52 ± 0.11 mL/h/kg BW) rats (p = .005). The percentage of unmetabolized parent was significantly different between both sexes at 20 min and 60 min p.i. In the liver, a 1.6-fold higher radioactivity concentration was found in male versus female animals and in addition also the percentage of unmetabolized parent was different.

Conclusion: Our results show pronounced sex differences in blood/plasma pharmacokinetics and metabolism of [F]THK-5317 in rats. Female animals showed a faster plasma clearance compared to males. These results underline the importance of investigating both sexes and also support the notion that individual input functions or sex-specific population-based input functions are needed for kinetic modeling analyses.

Advances In Knowledge: First preclinical study in rats showing pronounced sex differences in blood/plasma pharmacokinetics and metabolism of [F]THK-5317.

Implications For Patient Care: Sex-specific differences might also be present in humans and thus clinical trials should have adequate sample size to account for effects in men and women separately.
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http://dx.doi.org/10.1016/j.nucmedbio.2020.01.001DOI Listing
January 2020

PET Imaging of Astrogliosis and Tau Facilitates Diagnosis of Parkinsonian Syndromes.

Front Aging Neurosci 2019 11;11:249. Epub 2019 Sep 11.

Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.

Neurodegenerative parkinsonian syndromes comprise a number of disorders that are characterized by similar clinical features but are separated on the basis of different pathologies, i.e., aggregates of α-synuclein or tau protein. Due to the overlap of signs and symptoms a precise differentiation is often difficult, especially early in the disease course. Enormous efforts have been taken to develop tau-selective PET imaging agents, but strong off-target binding to monoamine oxidase B (MAO-B) has been observed across first generation ligands. Nonetheless, astrogliosis-related MAO-B elevation is a common histopathological known feature of all parkinsonian syndromes and might be itself an interesting imaging target. Therefore, this study aimed to investigate the performance of [F]-THK5351, a combined MAO-B and tau tracer for differential diagnosis of parkinsonian syndromes. [F]-THK5351 PET was performed in 34 patients: six with Parkinson's disease (PD), nine with multiple system atrophy with predominant parkinsonism (MSA-P), six with MSA with predominant cerebellar ataxia (MSA-C), and 13 with progressive supranuclear palsy (PSP) Richardson's syndrome. Volume-of-interest-based quantification of standardized-uptake-values was conducted in different parkinsonian syndrome-related target regions. PET results were subjected to multinomial logistic regression to create a prediction model discriminating among groups. Furthermore, we correlated tracer uptake with clinical findings. Elevated [F]-THK5351 uptake in midbrain and diencephalon differentiated PSP patients from PD and MSA-C. MSA-C patients were distinguishable by high tracer uptake in the pons and cerebellar deep white matter when compared to PSP and PD patients, whereas MSA-P patients tended to show higher tracer uptake in the lentiform nucleus. A multinomial logistic regression classified 33/34 patients into the correct clinical diagnosis group. Tracer uptake in the pons, cerebellar deep white matter, and striatum was closely associated with the presence of cerebellar and parkinsonian symptoms of MSA patients. The current study demonstrates that combined MAO-B and tau binding of THK5351 facilitates differential diagnosis of parkinsonian syndromes. Furthermore, our data indicate a correlation of MSA phenotype with [F]-THK5351 uptake in certain brain regions, illustrating their relevance for the emergence of clinical symptoms and underlining the potential of THK5351 PET as a biomarker that correlates with pathological changes as well as with disease stage.
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http://dx.doi.org/10.3389/fnagi.2019.00249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749151PMC
September 2019

Topographical Heterogeneity of Alzheimer's Disease Based on MR Imaging, Tau PET, and Amyloid PET.

Front Aging Neurosci 2019 20;11:211. Epub 2019 Aug 20.

Department of Neurology, Gil Medical Center, Gachon University College of Medicine, Incheon, South Korea.

Alzheimer's disease (AD) patients are known to have heterogeneous clinical presentation and pathologic patterns. We hypothesize that AD dementia can be categorized into subtypes based on multimodal imaging biomarkers such as magnetic resonance imaging (MRI), tau positron emission tomography (PET), and amyloid PET. We collected 3T MRI, F-THK5351 PET, and F-flutemetamol (FLUTE) PET data from 83 patients with AD dementia [Clinical Dementia Rating (CDR) ≤1] and 60 normal controls (NC), and applied surface-based analyses to measure cortical thickness, THK5351 standardized uptake value ratio (SUVR) and FLUTE SUVR for each participant. For the patient group, we performed an agglomerative hierarchical clustering analysis using the three multimodal imaging features on the vertices ( = 3 × 79,950). The identified AD subtypes were compared to NC using general linear models adjusting for age, sex, and years of education. We mapped the effect size within significant cortical regions reaching a corrected -vertex <0.05 (random field theory). Our surface-based multimodal framework has revealed three distinct subtypes among AD patients: medial temporal-dominant subtype (MT, = 44), parietal-dominant subtype (P, = 19), and diffuse atrophy subtype (D, = 20). The topography of cortical atrophy and THK5351 retention differentiates between the three subtypes. In the case of FLUTE, three subtypes did not show distinct topographical differences, although cortical composite retention was significantly higher in the P type than in the MT type. These three subtypes also differed in demographic and clinical features. In conclusion, AD patients may be clustered into three subtypes with distinct topographical features of cortical atrophy and tau deposition, although amyloid deposition may not differ across the subtypes in terms of topography.
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http://dx.doi.org/10.3389/fnagi.2019.00211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710378PMC
August 2019

Brain histamine H receptor occupancy after oral administration of desloratadine and loratadine.

Pharmacol Res Perspect 2019 08 12;7(4):e00499. Epub 2019 Jul 12.

Division of Pharmacology, Faculty of Medicine Tohoku Medical and Pharmaceutical University Sendai Japan.

Some histamine H receptor (HR) antagonists induce adverse sedative reactions caused by blockade of histamine transmission in the brain. Desloratadine is a second-generation antihistamine for treatment of allergic disorders. Its binding to brain HRs, which is the basis of sedative property of antihistamines, has not been examined previously in the human brain by positron emission tomography (PET). We examined brain HR binding potential ratio (BPR), HR occupancy (HRO), and subjective sleepiness after oral desloratadine administration in comparison to loratadine. Eight healthy male volunteers underwent PET imaging with [C]-doxepin, a PET tracer for HRs, after a single oral administration of desloratadine (5 mg), loratadine (10 mg), or placebo in a double-blind crossover study. BPR and HRO in the cerebral cortex were calculated, and plasma concentrations of loratadine and desloratadine were measured. Subjective sleepiness was quantified by the Line Analogue Rating Scale (LARS) and the Stanford Sleepiness Scale (SSS). BPR was significantly lower after loratadine administration than after placebo (0.504 ± 0.074 vs 0.584 ± 0.059 [mean ± SD], <0.05), but BPR after desloratadine administration was not significantly different from BPR after placebo (0.546 ± 0.084 vs 0.584 ± 0.059, = 0.250). The plasma concentration of loratadine was negatively correlated with BPR in subjects receiving loratadine, but that of desloratadine was not correlated with BPR. Brain HROs after desloratadine and loratadine administration were 6.47 ± 10.5% and 13.8 ± 7.00%, respectively (=0.103). Subjective sleepiness did not significantly differ among subjects receiving the two antihistamines and placebo. At therapeutic doses, desloratadine did not bind significantly to brain HRs and did not induce any significant sedation.
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http://dx.doi.org/10.1002/prp2.499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624455PMC
August 2019

Assessment of Amyloid Deposition in Patients With Probable REM Sleep Behavior Disorder as a Prodromal Symptom of Dementia With Lewy Bodies Using PiB-PET.

Front Neurol 2019 25;10:671. Epub 2019 Jun 25.

Department of Psychiatry, Yamagata University School of Medicine, Yamagata, Japan.

Dementia with Lewy bodies (DLB) often exhibits REM sleep behavior disorder (RBD) at its prodromal stage. Meanwhile, DLB is often comorbid with Alzheimer's disease (AD)-type pathology. In typical AD, amyloid-β deposition begins considerably before the onset of dementia and has already reached a plateau at the stage of mild cognitive impairment. However, it is not known when amyloid accumulation starts in DLB with AD-type pathology. In the present study, we examined amyloid deposition in patients with RBD as a prodromal symptom of DLB using [11C]-Pittsburgh compound B positron emission tomography (PiB-PET). The subjects were 12 patients with probable RBD as diagnosed by the Japanese RBD screening questionnaire. They also showed abnormality in 123I-metaiodobenzylguanidine myocardial scintigraphy, a biomarker for DLB. For comparison, 11 patients with probable DLB were included. Applying PMOD software to the PiB-PET images, the global cortical distribution volume ratio was calculated and a ratio >1.3 was regarded as PiB-positive. Two of the RBD patients (16.7%) and eight of the DLB patients (72.7%) were PiB-positive. The amyloid-positive rate was significantly lower in the RBD group than in the DLB group ( = 0.012). The prevalence of amyloid deposition in RBD as a prodromal symptom of DLB was significantly lower than that in DLB, suggesting that amyloid accumulation does not always begin at the early stage of DLB.
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http://dx.doi.org/10.3389/fneur.2019.00671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603167PMC
June 2019

Determination of Short-Chain Fatty Acids in Mouse Feces by High-Performance Liquid Chromatography Using 2-Nitrophenylhydrazine as a Labeling Reagent.

Biol Pharm Bull 2019 ;42(5):845-849

Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University.

It has been suggested that imbalances in gut microbiota are related to diseases associated with metabolism, the central nervous system, etc. Therefore, analysis of short-chain fatty acids (SCFAs) produced by gut microbiota is very important as an indicator of causation, demonstrating the effects on the host due to changes in the gut microbiota. We developed a HPLC method for the determination of SCFAs in mouse feces. After homogenization, the SCFAs in mouse feces and 2-ethylbutyric acid (internal standard) were derivatized with 2-nitrophenylhydrazine (2-NPH) in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The 2-NPH derivatives of SCFAs and the internal standard were separated on a reversed-phase column (octadecyl silyl column) by gradient elution using phosphoric acid (pH 2.5)-acetonitrile at 50°C and detected by absorbance measurement at 400 nm. The recovery of the method was 90-115%, with a precision (relative standard deviation) of 1.3-7.7%. The determination of SCFAs by the present method can provide useful information for biological and clinical research.
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http://dx.doi.org/10.1248/bpb.b18-01017DOI Listing
September 2019

F-THK5351 PET Imaging in Nonfluent-Agrammatic Variant Primary Progressive Aphasia.

Dement Neurocogn Disord 2018 Sep 10;17(3):110-119. Epub 2018 Dec 10.

Department of Neurology, Gachon University Gil Medical Center, Incheon, Korea.

Background And Purpose: To analyze F-THK5351 positron emission tomography (PET) scans of patients with clinically diagnosed nonfluent/agrammatic variant primary progressive aphasia (navPPA).

Methods: Thirty-one participants, including those with Alzheimer's disease (AD, =13), navPPA (=3), and those with normal control (NC, =15) who completed 3 Tesla magnetic resonance imaging, F-THK5351 PET scans, and detailed neuropsychological tests, were included. Voxel-based and region of interest (ROI)-based analyses were performed to evaluate retention of F-THK5351 in navPPA patients.

Results: In ROI-based analysis, patients with navPPA had higher levels of THK retention in the Broca's area, bilateral inferior frontal lobes, bilateral precentral gyri, and bilateral basal ganglia. Patients with navPPA showed higher levels of THK retention in bilateral frontal lobes (mainly left side) compared than NC in voxel-wise analysis.

Conclusions: In our study, THK retention in navPPA patients was mainly distributed at the frontal region which was well correlated with functional-radiological distribution of navPPA. Our results suggest that tau PET imaging could be a supportive tool for diagnosis of navPPA in combination with a clinical history.
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http://dx.doi.org/10.12779/dnd.2018.17.3.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428011PMC
September 2018

Daiokanzoto (Da-Huang-Gan-Cao-Tang) is an effective laxative in gut microbiota associated with constipation.

Sci Rep 2019 03 7;9(1):3833. Epub 2019 Mar 7.

Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, 1 Sanzo, Gakuen-cho, Fukuyama, Hiroshima, 729-0292, Japan.

Interindividual differences affect the purgative activities of sennoside A (SA) and Daiokanzoto (Da-Huang-Gan-Cao-Tang, DKT). In this study, we manipulated gut microbiota in mice to establish laxative responders and non-responders by feeding them a high-carbohydrate, a high-fat or a high-fibre diet. To assess the relationship between laxatives and gut microbiota, we monitored the gut microbiota before and after administering laxatives. Twenty mice per diet were divided into four groups of five mice to evaluate purgative activities of four laxative preparations, DKT, SA, SA plus rhein 8-O-β-D-glucopyranoside (SA + RG), and SA plus liquiritin (SA + LQ). Gut microbiota changes were monitored by next-generation sequencing of 16 S rRNA gene amplicons. In high-carbohydrate and high-fat diet-fed mice, DKT exerted a significantly higher purgative activity than SA alone, and RG contributed to this activity. DKT and SA + RG administration increased the Enterobacteriaceae content of gut microbiota, which was associated with an increased purgative activity. In contrast, DKT activity was significantly suppressed by high-fibre diet. Hence, diet-induced differences in gut microbiota determined the effect of DKT, which is interesting, considering that Oriental medicines are formulated for a specific functional state or "pattern". These results demonstrated that the purgative activity of anthranoid laxatives is susceptible to diet-induced alterations in gut microbiota.
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http://dx.doi.org/10.1038/s41598-019-40278-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405880PMC
March 2019

Association of deposition of tau and amyloid-β proteins with structural connectivity changes in cognitively normal older adults and Alzheimer's disease spectrum patients.

Brain Behav 2018 12 24;8(12):e01145. Epub 2018 Oct 24.

Integrative Brain Imaging Center, National Center of Neurology and Psychiatry, Tokyo, Japan.

Introduction: Alzheimer's disease (AD) is characterized by accumulation of extracellular amyloid-β and intracellular tau neurofibrillary tangles. The recent advent of tau positron emission tomography (PET) has enabled in vivo assessment of tau pathology. The aim of this study was to explore whether tau deposition influences the structural connectivity in amyloid-negative and amyloid-positive groups, and further explore the difference between the groups.

Methods: We investigated 18 patients with amnestic mild cognitive impairment/mild AD (AD-spectrum group) and 35 cognitively normal older adults (CN group) using diffusion MRI, amyloid, and tau PET imaging. Diffusion connectometry was performed to identify white matter pathways correlated with each of the six variables of tau deposition in the bilateral hippocampi, temporal lobes, posterior and anterior cingulate cortices, precunei, orbitofrontal lobes, and entire cerebrum.

Results: The CN group showed increased connectivity along with an increased tau deposition in the bilateral hippocampi, temporal lobes, and entire cerebrum, whereas the AD-spectrum group showed decreased connectivity in the bilateral hippocampi, temporal lobes, anterior and posterior cingulate cortices, precunei, and entire cerebrum.

Conclusion: These findings suggest that tau deposition in the CN group seems to induce a compensatory response against early neuronal injury or chronic inflammation associated with normal aging, whereas the coexistence of amyloid and tau in the AD-spectrum group seems to outweigh the compensatory response leading to decreased connectivity, suggesting that amyloid plays a crucial role in alternating structural connectivity.
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http://dx.doi.org/10.1002/brb3.1145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305935PMC
December 2018

Involvement of the Precuneus/Posterior Cingulate Cortex Is Significant for the Development of Alzheimer's Disease: A PET (THK5351, PiB) and Resting fMRI Study.

Front Aging Neurosci 2018 5;10:304. Epub 2018 Oct 5.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

: Imaging studies in Alzheimer's disease (AD) have yet to answer the underlying questions concerning the relationship among tau retention, neuroinflammation, network disruption and cognitive decline. We compared the spatial retention patterns of F-THK5351 and resting state network (RSN) disruption in patients with early AD and healthy controls. : We enrolled 23 C-Pittsburgh compound B (PiB)-positive patients with early AD and 24 C-PiB-negative participants as healthy controls. All participants underwent resting state functional MRI and F-THK5351 PET scans. We used scaled subprofile modeling/principal component analysis (SSM/PCA) to reduce the complexity of multivariate data and to identify patterns that exhibited the largest statistical effects (variances) in THK5351 concentration in AD and healthy controls. : SSM/PCA identified a significant spatial THK5351 pattern composed by mainly three clusters including precuneus/posterior cingulate cortex (PCC), right and left dorsolateral prefrontal cortex (DLPFC) which accounted for 23.6% of the total subject voxel variance of the data and had 82.6% sensitivity and 79.1% specificity in discriminating AD from healthy controls. There was a significant relationship between the intensity of the F-THK5351 covariation pattern and cognitive scores in AD. The spatial patterns of F-THK5351 uptake showed significant similarity with intrinsic functional connectivity, especially in the PCC network. Seed-based connectivity analysis from the PCC showed significant decrease in connectivity over widespread brain regions in AD patients. An evaluation of an autopsied AD patient with Braak V showed that F-THK5351 retention corresponded to tau deposition, monoamine oxidase-B (MAO-B) and astrogliosis in the precuneus/PCC. : We identified an AD-specific spatial pattern of F-THK5351 retention in the precuneus/PCC, an important connectivity hub region in the brain. Disruption of the functional connections of this important network hub may play an important role in developing dementia in AD.
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http://dx.doi.org/10.3389/fnagi.2018.00304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182068PMC
October 2018

Corrigendum: Imaging Protein Misfolding in the Brain Using β-Sheet Ligands.

Front Neurosci 2018 25;12:675. Epub 2018 Sep 25.

Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan.

[This corrects the article DOI: 10.3389/fnins.2018.00585.].
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http://dx.doi.org/10.3389/fnins.2018.00675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190880PMC
September 2018

Investigation of the quantitative accuracy of low-dose amyloid and tau PET imaging.

Radiol Phys Technol 2018 Dec 16;11(4):451-459. Epub 2018 Oct 16.

Division of Radiation Informatics for Medical Imaging, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan.

With the increasing incidence of dementia worldwide, the frequent use of amyloid and tau positron emission tomography imaging requires low-dose protocols for the differential diagnoses of various neurodegenerative diseases and the monitoring of disease progression. In this study, we investigated the feasibility to reduce the PET dose without a significant loss of quantitative accuracy in 3D dynamic row action maximum likelihood algorithm-reconstructed PET images using [C]PIB and [F]THK5351. Eighteen cognitively normal young controls, cognitively normal elderly controls, and patients with probable Alzheimer's disease (n = 6 each), were included. Reduced doses were simulated by randomly sampling half and quarter of the full counts in list mode data for one independent realization at each simulated dose. Bias was evaluated between the reduced dose from the full dose of standardized uptake value ratio (SUVR), distribution volume ratio (DVR) from reference Logan, and non-displaceable binding potential (BP) from simplified reference tissue model (SRTM). DVR yielded the least bias at low dose compared to SUVR and BP, and thus, is highly recommended. The dose of [F]THK5351 and [C]PIB can be reduced to a quarter of the full dose using DVR for evaluation, whereas the dose can only be reduced to half and a quarter of the full dose for [F]THK5351 and [C]PIB using SUVR. BP showed inconsistent trend and large bias at low dose. The feasibility of dose reduction was dependent on the selected parameters of interest, reconstruction algorithms, reference regions, and to a lesser degree by motion effects.
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http://dx.doi.org/10.1007/s12194-018-0485-yDOI Listing
December 2018

Imaging Protein Misfolding in the Brain Using β-Sheet Ligands.

Front Neurosci 2018 21;12:585. Epub 2018 Aug 21.

Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Neurodegenerative diseases characterized by pathological protein accumulation in cells are termed "proteinopathies." Although various protein aggregates share cross-β-sheet structures, actual conformations vary among each type of protein deposit. Recent progress in the development of radiotracers for positron emission tomography (PET) has enabled the visualization of protein aggregates in living brains. Amyloid PET tracers have been developed, and are widely used for the diagnosis of Alzheimer's disease and non-invasive assessment of amyloid burden in clinical trials of anti-dementia drugs. Furthermore, several tau PET tracers have been successfully developed and used in the clinical studies. However, recent studies have identified the presence of off-target binding of radiotracers in areas of tau deposition, suggesting that concomitant neuroinflammatory changes might affect tracer binding. In contrast to amyloid and tau PET, there are no established tracers for imaging Lewy bodies in the human brain. In this review, we describe lessons learned from the development of PET tracers and discuss the future direction of tracer development for protein misfolding diseases.
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http://dx.doi.org/10.3389/fnins.2018.00585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110819PMC
August 2018

Targeting metals rescues the phenotype in an animal model of tauopathy.

Metallomics 2018 09;10(9):1339-1347

The Florey Institute for Neuroscience and Mental Health and The University of Melbourne, Parkville, 30 Royal Parade, Victoria 3052, Australia.

Tauopathies are characterized by the pathological accumulation of the microtubule associated protein tau within the brain. We demonstrate here that a copper/zinc chaperone (PBT2, Prana Biotechnology) has rapid and profound effects in the rTg(tauP301L)4510 mouse model of tauopathy. This was evidenced by significantly improved cognition, a preservation of neurons, a decrease in tau aggregates and a decrease in other forms of "pathological" tau (including phosphorylated tau and sarkosyl-insoluble tau). Our data demonstrate that one of the primary mechanisms of action of PBT2 in this model may be driven by an interaction on the pathways responsible for the dephosphorylation of tau. Specifically, PBT2 increased protein levels of both the structural and catalytic subunits of protein phosphatase 2A (PP2A), decreased levels of the methyl esterase (PME1) that dampens PP2A activity, and increased levels of the prolyl isomerase (Pin1) that stimulates the dephosphorylation activity of PP2A. None of these effects were observed when the metal binding site of PBT2 was blocked. This highlights the potential utility of targeting metal ions as a novel therapeutic strategy for diseases in which tau pathology is a feature, which includes conditions such as frontotemporal dementia and Alzheimer's disease.
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http://dx.doi.org/10.1039/c8mt00153gDOI Listing
September 2018

The development and validation of tau PET tracers: current status and future directions.

Clin Transl Imaging 2018 20;6(4):305-316. Epub 2018 Jul 20.

3Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.

Purpose: To provide an overview on positron emission tomography (PET) imaging of tau pathology in Alzheimer's disease (AD) and other neurodegenerative disorders.

Results: Different classes of tau tracers such as flortaucipir, THK5317, and PBB3 have been developed and utilized in previous clinical studies. In AD, the topographical distribution of tracer binding follows the known distribution of neurofibrillary tangles and is closely associated with neurodegeneration as well as the clinical phenotype of dementia. Significant retention of tracers has also been observed in the frequent site of the 4-repeat (4R) tau isoform deposits in non-AD tauopathies, such as in progressive supranuclear palsy. However, in vitro binding studies indicate that most tau tracers are less sensitive to straight tau filaments, in contrast to their high binding affinity to paired helical filaments of tau (PHF-tau). The first-generation of tau tracers shows off-target binding in the basal ganglia, midbrain, thalamus, choroid plexus, and venous sinus. Off-target binding of THK5351 to monoamine oxidase B (MAO-B) has been observed in disease-associated brain regions linked to neurodegeneration and is associated with astrogliosis in areas of misfolded protein accumulation. The second generation of tau tracers, such as [F]MK-6240, is highly selective to PHF-tau with little off-target binding and have enabled the reliable assessment of PHF-tau burden in aging and AD.

Conclusions: Tau PET tracers have enabled in vivo quantification of PHF-tau burden in human brains. Tau PET can help in understanding the underlying cause of dementia symptoms, and in patient selection for clinical trials of anti-dementia therapies.
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http://dx.doi.org/10.1007/s40336-018-0290-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096533PMC
July 2018

[F]THK-5351 PET imaging in early-stage semantic variant primary progressive aphasia: a report of two cases and a literature review.

BMC Neurol 2018 Aug 8;18(1):109. Epub 2018 Aug 8.

Department of Psychiatry, Yamagata University School of Medicine, 2-2-2 Iidanishi, Yamagata City, Yamagata, 990-9585, Japan.

Background: Semantic variant primary progressive aphasia (svPPA) is a subtype of primary progressive aphasia characterized by two-way anomia and disturbance in word comprehension, with focal atrophy in the left temporal lobe. [F]THK-5351 was originally developed to trace tau protein. However, it has recently been suggested that [F]THK-5351 binds to monoamine oxidase B in astrocytes, which reflects gliosis. Herein, the authors present two cases involving patients with early-stage svPPA who underwent [F]THK-5351 positron emission tomography (PET) imaging, and examined whether [F]THK-5351 PET imaging is more sensitive to neurodegenerative lesions than conventional imaging modalities such as magnetic resonance imaging (MRI) and cerebral blood flow (CBF)-single photon emission computed tomography (SPECT).

Case Presentation: Two patients, 64- and 79-year-old men, without notable medical or family history, exhibited disturbances in word comprehension and mild anomia with fluent speech and spared repetition. In both cases, surface dyslexia was observed but prosopagnosia was absent. Although mild depression was detected in 1 of the 2 patients, no behavioral disorders were present in either case. In both cases, MRI revealed atrophy in the anterior and inferior portions of the left temporal lobe. Technetium-99-ethyl cysteinate dimer ([Tc]ECD) SPECT revealed hypoperfusion in the left temporal lobe. Alzheimer's disease was ruled out by [C]Pittsburgh Compound-B (PiB) PET scan. Both patients fulfilled the diagnostic criteria for svPPA. Because of mild language deficits and lack of right temporal atrophy, they were considered to be at an early stage of the disease. In both cases, [F]THK-5351 retention was observed in bilateral temporal lobes, predominantly on the left side. Comparison of different imaging modalities suggested that [F]THK-5351 was more sensitive in detecting neurodegenerative change in the right temporal lobe than MRI and [Tc]ECD SPECT.

Conclusions: [F]THK-5351 retention was clearly demonstrated at an early stage of svPPA. Results of the present study suggest that [F]THK-5351 PET imaging may facilitate very early diagnosis of the disease.
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http://dx.doi.org/10.1186/s12883-018-1115-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205153PMC
August 2018

Dissociation of Tau Deposits and Brain Atrophy in Early Alzheimer's Disease: A Combined Positron Emission Tomography/Magnetic Resonance Imaging Study.

Front Aging Neurosci 2018 18;10:223. Epub 2018 Jul 18.

Integrative Brain Imaging Center, National Center of Neurology and Psychiatry, Tokyo, Japan.

The recent advent of tau-specific positron emission tomography (PET) has enabled assessment of tau pathology in Alzheimer's disease (AD). However, because PET scanners have limited spatial resolution, the measured signals of small brain structures or atrophied areas are underestimated by partial volume effects (PVEs). The aim of this study was to determine whether partial volume correction (PVC) improves the precision of measures of tau deposits in early AD. We investigated tau deposits in 18 patients with amyloid-positive early AD and in 36 amyloid-negative healthy controls using F-THK5351 PET. For PVC, we applied the SPM toolbox PETPVE12. The PET images were then spatially normalized and subjected to voxel-based group analysis using SPM12 for comparison between the early AD patients and healthy controls. We also compared these two groups in terms of brain atrophy using voxel-based morphometry of MRI. We found widespread neocortical tracer retention predominantly in the posterior cingulate and precuneus areas, but also in the inferior temporal lobes, inferior parietal lobes, frontal lobes, and occipital lobes in the AD patients compared with the controls. The pattern of tracer retention was similar between before and after PVC, suggesting that PVC had little effect on the precision of tau load measures. Gray matter atrophy was detected in the medial/lateral temporal lobes and basal frontal lobes in the AD patients. Interestingly, only a few associations were found between atrophy and tau deposits, even after PVC. In conclusion, PVC did not significantly affect F-THK5351 PET measures of tau deposits. This discrepancy between tau deposits and atrophy suggests that tau load precedes atrophy.
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http://dx.doi.org/10.3389/fnagi.2018.00223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058018PMC
July 2018

Visualization of ischemic stroke-related changes on F-THK-5351 positron emission tomography.

EJNMMI Res 2018 Jul 16;8(1):62. Epub 2018 Jul 16.

Department of Neurology, Chang Gung Memorial Hospital, Taoyuan City, Taiwan.

Background: The F-THK-5351 radiotracer has been used to detect the in vivo tau protein distribution in patients with tauopathy, such as Alzheimer's disease and corticobasal syndrome. In addition, F-THK-5351 can also monitor neuroinflammatory process due to high affinity to astrogliosis. We aimed to explore F-THK-5351 distribution patterns and characteristics in patients with recent ischemic stroke.

Results: Fifteen patients received F-THK-5351 positron emission tomography (PET) and diffusion tensor imaging (DTI) approximately 3 months after ischemic stroke. A region of interest (ROI) was placed in the peri-ischemic area and was mirrored on the contralateral side as the control, and a proportional value was derived from the ratio of the peri-ischemic ROI value over the mirrored ROI value. Increased F-THK-5351 retention was observed in the areas around and remote from the stroke location. The proportional F-THK-5351 values were negatively correlated with the proportional fractional anisotropy values (r = - 0.39, P = 0.04).

Conclusion: F-THK-5351 PET imaging provides a potential tool for in vivo visualization of the widespread ischemia-related changes associated with a microstructural disruption in recent ischemic stroke patients.
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http://dx.doi.org/10.1186/s13550-018-0417-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047954PMC
July 2018

IgLON5: A case with predominant cerebellar tau deposits and leptomeningeal inflammation.

Neurology 2018 07 3;91(4):180-182. Epub 2018 Jul 3.

From the Department of Neurology (F.S., J.L., J.R., N.G., O.E.), German Center for Vertigo and Balance Disorders, DSGZ (F.S.), and Department of Nuclear Medicine (M.U., A.R., N.A., M.B.), Ludwig-Maximilians-University; German Center for Neurodegenerative Diseases (J.L.), DZNE, Munich, Germany; and Division of Pharmacology (N.O.), Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Japan.

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http://dx.doi.org/10.1212/WNL.0000000000005859DOI Listing
July 2018

Neuroimaging-pathological correlations of [F]THK5351 PET in progressive supranuclear palsy.

Acta Neuropathol Commun 2018 06 29;6(1):53. Epub 2018 Jun 29.

Department of Geriatrics and Gerontology, Division of Brain Science, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan.

Recent positron emission tomography (PET) studies have demonstrated the accumulation of tau PET tracer in the affected region of progressive supranuclear palsy (PSP) cases. To confirm the binding target of radiotracer in PSP, we performed an imaging-pathology correlation study in two autopsy-confirmed PSP patients who underwent [F]THK5351 PET before death. One patient with PSP Richardson syndrome showed elevated tracer retention in the globus pallidus and midbrain. In a patient with PSP-progressive nonfluent aphasia, [F]THK5351 retention also was observed in the cortical areas, particularly the temporal cortex. Neuropathological examination confirmed PSP in both patients. Regional [F]THK5351 standardized uptake value ratio (SUVR) in antemortem PET was significantly correlated with monoamine oxidase-B (MAO-B) level, reactive astrocytes density, and tau pathology at postmortem examination. In in vitro autoradiography, specific THK5351 binding was detected in the area of antemortem [F]THK5351 retention, and binding was blocked completely by a reversible selective MAO-B inhibitor, lazabemide, in brain samples from these patients. In conclusion, [F]THK5351 PET signals reflect MAO-B expressing reactive astrocytes, which may be associated with tau accumulation in PSP.
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http://dx.doi.org/10.1186/s40478-018-0556-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025736PMC
June 2018

Comparison of F-T807 and F-THK5117 PET in a Mouse Model of Tau Pathology.

Front Aging Neurosci 2018 7;10:174. Epub 2018 Jun 7.

Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany.

Positron-emission-tomography (PET) imaging of tau pathology has facilitated development of anti-tau therapies. While members of the arylquinoline and pyridoindole families have been the most frequently used tau radioligands so far, analyses of their comparative performance are scantly documented. Here, we conducted a head-to-head PET comparison of the arylquinoline FT807 and the pyridoindole FTHK5117 PET in a mouse model of tau pathology. PET recordings were obtained in groups of ( = 5-7) P301S and wild-type (WT) mice at 6 and 9 months of age. Volume-of-interest based analysis (standard-uptake-value ratio, SUVR) was used to calculate effect sizes (Cohen's ) for each tracer and age. Statistical parametric mapping (SPM) was used to assess regional similarity (dice coefficient) of tracer binding alterations for the two tracers. Immunohistochemistry staining of neurofibrillary tangles was performed for validation . Significantly elevated F-T807 binding in the brainstem of P301S mice was already evident at 6 months (+14%, < 0.01, = 1.64), and increased further at 9 months (+23%, < 0.001, = 2.70). F-THK5117 indicated weaker increases and effect sizes at 6 months (+5%, < 0.05, = 1.07) and 9 months (+10%, < 0.001, = 1.49). Regional similarity of binding of the two tracers was high (71%) at 9 months. F-T807 was more sensitive than F-THK5117 to tau pathology in this model, although both tracers present certain obstacles, which need to be considered in the design of longitudinal preclinical tau imaging studies.
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http://dx.doi.org/10.3389/fnagi.2018.00174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999706PMC
June 2018