The neuromodulatory role of dopamine in improved reaction time by acute cardiovascular exercise.

Acute cardiovascular physical exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Here, using positron emission tomography (PET) with [11 C]raclopride, in a multi-experiment study we investigated whether acute exercise releases endogenous dopamine (DA) in the brain. We hypothesized that acute exercise augments the brain DA system, and that RT improvement is correlated with this endogenous DA release. The PET study (Experiment 1: n = 16) demonstrated that acute physical exercise released endogenous DA, and that endogenous DA release was correlated with improvements in RT of the Go/No-Go task. Thereafter, using two electrical muscle stimulation (EMS) studies (Experiments 2 and 3: n = 18 and 22 respectively), we investigated what triggers RT improvement. The EMS studies indicated that EMS with moderate arm cranking improved RT, but RT was not improved following EMS alone or EMS combined with no load arm cranking. The novel mechanistic findings from these experiments are: (1) endogenous DA appears to be an important neuromodulator for RT improvement and (2) RT is only altered when exercise is associated with central signals from higher brain centres. Our findings explain how humans rapidly alter their behaviour using neuromodulatory systems and have significant implications for promotion of cognitive health. KEY POINTS: Acute cardiovascular exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Using the neurochemical specificity of [11 C]raclopride positron emission tomography, we demonstrated that acute supine cycling released endogenous dopamine (DA), and that this release was correlated with improved RT. Additional electrical muscle stimulation studies demonstrated that peripherally driven muscle contractions (i.e. exercise) were insufficient to improve RT. The current study suggests that endogenous DA is an important neuromodulator for RT improvement, and that RT is only altered when exercise is associated with central signals from higher brain centres.

The quantification of muscle activities during arm elevation following reverse shoulder arthroplasty or superior capsular reconstruction for irreparable rotator cuff tears using positron emission tomography.

BACKGROUND: Reverse shoulder arthroplasty (RSA) and superior capsular reconstruction (SCR) are recognized as surgical options for an irreparable rotator cuff tear. However, the postoperative changes of the muscle activity patterns remain unclear. The purpose of this study was to investigate the quantified muscle activities on shoulder elevation in patients treated with RSA or SCR using fluorine-18-labelled fluorodeoxyglucose-positron emission tomography. METHODS: Asymptomatic shoulders that underwent RSA or SCR and those without a rotator cuff tear were analyzed as the RSA, SCR, and control groups. All subjects underwent shoulder elevation exercise, followed by a fluorine-18-labelled fluorodeoxyglucose-positron emission tomography examination. Using previously established methods to quantify the uptake of each muscle on positron emission tomography images, the standard uptake values (SUVs) for 16 portions of the deltoid, rotator cuff, and periscapular muscles were obtained to compare the muscle activity patterns among 3 groups. RESULTS: The deltoid muscle showed the most characteristic differences according to the surgeries. The mean SUVs of the anterior, middle, and posterior deltoid were 3.3, 3.7, and 1.5 for the RSA group; 2.7, 4.2, and 1.5 for the SCR group; and 1.3, 2.0, and 0.9 for the control group, respectively. In comparison to the control group, both the RSA and SCR groups showed significantly increased SUVs at all portions of the deltoid muscle. The RSA group showed similar SUVs for the anterior and middle deltoid, whereas the SCR and control groups showed greatest SUVs at the middle deltoid. In addition, the serratus anterior, levator scapulae, and upper portion of the trapezius in the RSA group showed greater SUVs than in the control group. CONCLUSION: The deltoid muscle showed increased activity in the RSA and SCR groups. The middle deltoid was mainly used in the SCR group, whereas the anterior and middle deltoid, as well as the upward rotator muscles of the scapula, were mainly used in the RSA group.

18F-THK5351 Positron Emission Tomography Imaging in Neurodegenerative Tauopathies.

Introduction: We aimed to determine whether in vivo tau deposits and monoamine oxidase B (MAO-B) detection using 18F-THK5351 positron emission tomography (PET) can assist in the differential distribution in patients with corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD) and whether 18F-THK5351 retention of lesion sites in CBS and PSP can correlate with clinical parameters. Methods: 18F-THK5351 PET was performed in 35 participants, including 7, 9, and 10 patients with CBS, PSP, and AD, respectively, and 9 age-matched normal controls. In CBS and PSP, cognitive and motor functions were assessed using the Montreal Cognitive Assessment, Addenbrooke's Cognitive Examination-Revised, and Frontal Assessment Battery, Unified Parkinson's Disease Rating Scale Motor Score, and PSP Rating Scale. Results: 18F-THK5351 retention was observed in sites susceptible to disease-related pathologies in CBS, PSP, and AD. 18F-THK5351 uptake in the precentral gyrus clearly differentiated patients with CBS from those with PSP and AD. Furthermore, 18F-THK5351 uptake in the inferior temporal gyrus clearly differentiated patients with AD from those with CBS and PSP. Regional 18F-THK5351 retention was associated with the cognitive function in CBS and PSP. Conclusion: Measurement of the tau deposits and MAO-B density in the brain using 18F-THK5351 may be helpful for the differential diagnosis of tauopathies and for understanding disease stages.

Error propagation analysis of seven partial volume correction algorithms for [18F]THK-5351 brain PET imaging.

BACKGROUND: Novel partial volume correction (PVC) algorithms have been validated by assuming ideal conditions of image processing; however, in real clinical PET studies, the input datasets include error sources which cause error propagation to the corrected outcome. METHODS: We aimed to evaluate error propagations of seven PVCs algorithms for brain PET imaging with [18F]THK-5351 and to discuss the reliability of those algorithms for clinical applications. In order to mimic brain PET imaging of [18F]THK-5351, pseudo-observed SUVR images for one healthy adult and one adult with Alzheimer's disease were simulated from individual PET and MR images. The partial volume effect of pseudo-observed PET images were corrected by using Müller-Gärtner (MG), the geometric transfer matrix (GTM), Labbé (LABBE), regional voxel-based (RBV), iterative Yang (IY), structural functional synergy for resolution recovery (SFS-RR), and modified SFS-RR algorithms with incorporation of error sources in the datasets for PVC processing. Assumed error sources were mismatched FWHM, inaccurate image-registration, and incorrectly segmented anatomical volume. The degree of error propagations in ROI values was evaluated by percent differences (%diff) of PV-corrected SUVR against true SUVR. RESULTS: Uncorrected SUVRs were underestimated against true SUVRs (- 15.7 and - 53.7% in hippocampus for HC and AD conditions), and application of each PVC algorithm reduced the %diff. Larger FWHM mismatch led to larger %diff of PVC-SUVRs against true SUVRs for all algorithms. Inaccurate image registration showed systematic propagation for most algorithms except for SFS-RR and modified SFS-RR. Incorrect segmentation of the anatomical volume only resulted in error propagations in limited local regions. CONCLUSIONS: We demonstrated error propagation by numerical simulation of THK-PET imaging. Error propagations of 7 PVC algorithms for brain PET imaging with [18F]THK-5351 were significant. Robust algorithms for clinical applications must be carefully selected according to the study design of clinical PET data.

Muscle activities during shoulder internal rotation differ in arm position: a preliminary quantitative analysis using positron emission tomography.

OBJECTIVE: To investigate the muscle activity patterns of the glenohumeral joint during internal rotation both with the arm at 0° and 90° of abduction using 2-deoxy-2-[18F] fluoro-D-glucose (FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI). MATERIALS AND METHODS: Six healthy male volunteers underwent PET examination after performing active glenohumeral internal rotation exercise using an elastic band both with the arm at 0° and 90° of abduction. As a control, PET scan under resting condition was also performed. The exercise was performed before and after 18 fluorodeoxyglucose injection. Each PET image was fused to the corresponding MRI to identify each muscle. The standardized uptake value (SUV) of each muscle was compared between the two arm positions. RESULTS: With the arm at 0° of abduction, the SUV increased significantly after exercise both in the middle and inferior 1/3 of the subscapularis, which were significantly higher than that of the superior 1/3 of the subscapularis (P < 0.05). The SUV of the inferior 1/3 of the subscapularis was significantly higher at 90° of abduction than at 0° of abduction and was significantly higher than that of the superior 1/3 at 90° of abduction (P < 0.01). The SUV after exercise in the inferior infraspinatus and teres minor increased. CONCLUSIONS: The middle and inferior parts of the subscapularis are the main shoulder internal rotators in 0° of abduction, whereas the inferior part of the subscapularis is the main internal rotator in 90° of abduction.

Renal statistical map for positron emission tomography with [O-15] water.

Image statistics are frequently used for functional and molecular imaging research in which images from a patient group with a specific diagnosis are compared with images from a healthy control group who have been matched for demographic variables. The success of image statistics for brain imaging has encouraged us to develop a method for obtaining volumetrically normalized kidney to perform image statistics so that we can locally visualize the statistical significant difference comparing voxel by voxel between certain groups in terms kidney blood flow kinetic parameters. For the development of this evolutionary process, we first volumetrically normalized all subjects, which include healthy control (HC) and chronic renal failure (CRF) patients, 15O water PET image with respect to one HC subject's MRI image using affine transformation. Then 15O kinetic parametric images of normalized kidneys were obtained through the basis function method. Finally, the statistical map of these parametric images was produced using the threshold-free cluster enhancement based permutation method. Kinetic parameters of kidney namely, uptake rate constant (K1), clearance rate constant (k2) and blood volume (Va), were found to be notably lower in CRF than those of in HC and k2 parameter was found to be more stable compared to K1 and Va. The statistical map of these parametric images allowed us to visualize local significant differences statistically (P<0.05) between HC and CRF groups. Though PET and MRI techniques have enormous potentiality for functional and molecular imaging of kidney, these are, at best, in experimental level. It is speculated that statistical mapping of kidney could play a significant role in the successful implementation of functional and molecular kidney imaging. However, more research involving a larger sample size and improved normalization technique will be needed for the robustness of the process.

Error evaluation of the D-shuttle dosimeter technique in positron emission tomography study.

The D-shuttle dosimeter technique is a convenient approach for estimating the radiation dosimetry in a positron emission tomography (PET) study that employs multiple D-shuttle dosimeters attached to the body surface of a patient. To bring this technique into clinical usage, it is very important to evaluate its performance by investigating the bias associated with D-shuttle dosimeter positioning and by comparing the estimates with those of the whole-body dynamic PET imaging technique. The torso cavity and six spheres of the NEMA body phantom were filled with 18F-FDG solution, and then, the phantom was imaged for 1 h. We assumed the mislocated positioning of the D-shuttle dosimeters by shifting them in the z-direction (upper) in a range of 1-5 cm from the original positions. The cumulative radioactivities, absorbed doses, and effective dose were estimated using accurate and mislocated positions of the D-shuttle dosimeters. For comparison, the cumulative radioactivities were also estimated from the PET images, and then, the absorbed doses and effective dose were computed. The maximum bias of the average estimated cumulated radioactivities and the effective doses was - 15.0% and - 19.7% for the 1 cm shifted positions, respectively. The ratios of absorbed doses obtained from D-shuttle and PET measurement against the actual values were between 0.9 and 1.3, and 0.7 and 1.0, respectively. The bias associated with the D-shuttle dosimeter positions was significant and probably consistent, and both dosimetric techniques exhibited good performance in this phantom study.

A systematic performance evaluation of head motion correction techniques for 3 commercial PET scanners using a reproducible experimental acquisition protocol.

PURPOSES: Subject's motion during brain PET scan degrades spatial resolution and quantification of PET images. To suppress these effects, rigid-body motion correction systems have been installed in commercial PET scanners. In this study, we systematically compare the accuracy of motion correction among 3 commercial PET scanners using a reproducible experimental acquisition protocol. METHODS: A cylindrical phantom with two 22Na point sources was placed on a customized base to enable two types of motion, 5° yaw and 15° pitch rotations. Repetitive PET scans (5 min × 5 times) were performed at rest and under 2 motion conditions using 3 clinical PET scanners: the Eminence STARGATE G/L PET/CT (STARGATE) (Shimadzu Corp.), the SET-3000 B/X PET (SET-3000) (Shimadzu Corp.), and the Biograph mMR PET/MR (mMR) (Siemens Healthcare) systems. For STARGATE and SET-3000, the Polaris Vicra (Northern Digital Inc.) optical tracking system was used for frame-by-frame motion correction. For Biograph mMR, sequential MR images were simultaneously acquired with PET and used for LOR-based motion correction. All PET images were reconstructed by FBP algorithm with 1 × 1 mm pixel size. To evaluate the accuracy of motion correction, FWHMs and spherical ROI values were analyzed. RESULTS: The percent differences (%diff) in averaged FWHMs of point sources at 4 cm off-center between motion-corrected and static images were 0.77 ± 0.16 (STARGATE), 2.4 ± 0.34 (SET-3000), and 11 ± 1.0% (mMR) for a 5° yaw and 2.3 ± 0.37 (STARGATE) and 1.1 ± 0.60 (SET-3000) for a 15° pitch respectively. The averaged %diff between ROI values of motion-corrected images and static images were less than 2.0% for all conditions. CONCLUSIONS: In this study, we proposed a reproducible experimental framework to allow the systematic validation and comparison of multiple motion tracking and correction methodologies among different PET/CT and PET/MR commercial systems. Our proposed validation platform may be useful for future studies evaluating state-of-the-art motion correction strategies in clinical PET imaging.

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

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 [11C]PIB and [18F]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 (BPND) from simplified reference tissue model (SRTM). DVR yielded the least bias at low dose compared to SUVR and BPND, and thus, is highly recommended. The dose of [18F]THK5351 and [11C]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 [18F]THK5351 and [11C]PIB using SUVR. BPND 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.

Internal radiation dose estimation using multiple D-shuttle dosimeters for positron emission tomography (PET): A validation study using NEMA body phantom.

PURPOSE: Internal radiation dosimetry plays an important role in ensuring the safe use of positron emission tomography (PET) technology and is a legal requirement in most countries. We propose a new technique to estimate the internal radiation dose in PET studies by means of multiple D-shuttle dosimeters attached on the body surface of the patient. METHODS: Radioactivity in a source organ was estimated iteratively using measurements from multiple D-shuttle dosimeters with a maximum-likelihood expectation-maximization (MLEM) algorithm with dose response from a source to a D-shuttle dosimeter computed by Monte Carlo simulation. To validate our technique, we performed a phantom study using a National Electrical Manufacturers Association (NEMA) body phantom. The fillable compartments (torso cavity and six spheres) of the phantom were filled with 18 F-FDG mixed with pure water using an 800:1 sphere-to-background radioactivity concentration ratio. The radioactivity concentrations present in the torso cavity and six spheres were 0.00165 MBq/mL and 1.32 MBq/mL, respectively. The initial radioactivities of the torso cavity and six spheres (treated as source organs) were 15.9 MBq (torso cavity), 34.7 MBq (37 mm sphere), 15.1 MBq (28 mm sphere), 7.27 MBq (22 mm sphere), 3.26 MBq (17 mm sphere), 1.54 MBq (13 mm sphere), and 0.697 MBq (10 mm sphere). Eleven D-shuttle dosimeters were attached to the NEMA body phantom surface to obtain information on body surface dose and a mathematical NEMA body phantom has been modeled in the Heavy Ion Transport Code System (PHITS) Monte Carlo simulation code. RESULTS: Radioactivity was estimated in 2 min intervals over a 110-min total dose time using our proposed technique. A significant correlation (R2 = 0.992) was found between actual radioactivity and estimated radioactivity at every 2 min interval for each source organ. The estimated initial radioactivity (mean with standard deviation) was 16.5 ± 0.311 MBq (torso cavity), 33.0 ± 0.624 MBq (37 mm sphere), 15.7 ± 0.189 MBq (28 mm sphere), 7.11 ± 0.738 MBq (22 mm sphere), 4.17 ± 0.083 MBq (17 mm sphere), 1.48 ± 0.469 MBq (13 mm sphere), and 0.865 ± 0.313 MBq (10 mm sphere), which were very close to the actual initial radioactivity measurements for each source organ. CONCLUSIONS: The phantom study showed that our technique worked successfully. This technique could be used to estimate internal radiation dosimetry in a clinical PET study.

Neuroimaging-pathological correlations of [18F]THK5351 PET in progressive supranuclear palsy.

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 [18F]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, [18F]THK5351 retention also was observed in the cortical areas, particularly the temporal cortex. Neuropathological examination confirmed PSP in both patients. Regional [18F]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 [18F]THK5351 retention, and binding was blocked completely by a reversible selective MAO-B inhibitor, lazabemide, in brain samples from these patients. In conclusion, [18F]THK5351 PET signals reflect MAO-B expressing reactive astrocytes, which may be associated with tau accumulation in PSP.

Effects of levocetirizine and diphenhydramine on regional glucose metabolic changes and hemodynamic responses in the human prefrontal cortex during cognitive tasks.

OBJECTIVE: Antihistamines often have sedative side effects. This was the first study to measure regional cerebral glucose (energy) consumption and hemodynamic responses in young adults during cognitive tests after antihistamine administration. METHODS: In this double-blind, placebo-controlled, three-way crossover study, 18 healthy young Japanese men received single doses of levocetirizine 5 mg and diphenhydramine 50 mg at intervals of at least six days. Subjective feeling, task performances, and brain activity were evaluated during three cognitive tests (word fluency, two-back, and Stroop). Regional cerebral glucose consumption changes were measured using positron emission tomography with [18 F]fluorodeoxyglucose. Regional hemodynamic responses were measured using near-infrared spectroscopy. RESULTS: Energy consumption in prefrontal regions was significantly increased after antihistamine administration, especially diphenhydramine, whereas prefrontal hemodynamic responses, evaluated with oxygenated hemoglobin levels, were significantly lower with diphenhydramine treatment. Stroop test accuracy was significantly impaired by diphenhydramine, but not by levocetirizine. There was no significant difference in subjective sleepiness. CONCLUSIONS: Physiological "coupling" between metabolism and perfusion in the healthy human brain may not be maintained under pharmacological influence due to antihistamines. This uncoupling may be caused by a combination of increased energy demands in the prefrontal regions and suppression of vascular permeability in brain capillaries after antihistamine treatment. Further research is needed to validate this hypothesis.

Correlations of 18F-THK5351 PET with Postmortem Burden of Tau and Astrogliosis in Alzheimer Disease.

Clinical PET studies using 18F-THK5351 have demonstrated significant tracer retention in sites susceptible to tau burden in Alzheimer disease (AD). However, the in vivo PET signal to reflect tau aggregates remains controversial. Methods: We examined the spatial pattern of tracer binding, amyloid-ß, tau, and gliosis in an autopsy-confirmed AD patient who underwent 18F-THK5351 and 11C-Pittsburgh compound B PET before death. Results: Regional in vivo 18F-THK5351 retention was significantly correlated with the density of tau aggregates in the neocortex and monoamine oxidase-B in the whole brain, but not correlated with that of insoluble amyloid-ß. Furthermore, significant association was observed between the density of tau aggregates, monoamine oxidase-B, and glial fibrillary acidic protein, suggesting that neocortical tau would strongly influence the formation of reactive astrocytes. Conclusion:18F-THK5351 PET may have limited utility as a biomarker of tau pathology in AD; however, it could be used to monitor the neuroinflammatory processes in the living brain.

A comparison of five partial volume correction methods for Tau and Amyloid PET imaging with [18F]THK5351 and [11C]PIB.

PURPOSE: To suppress partial volume effect (PVE) in brain PET, there have been many algorithms proposed. However, each methodology has different property due to its assumption and algorithms. Our aim of this study was to investigate the difference among partial volume correction (PVC) method for tau and amyloid PET study. METHODS: We investigated two of the most commonly used PVC methods, Müller-Gärtner (MG) and geometric transfer matrix (GTM) and also other three methods for clinical tau and amyloid PET imaging. One healthy control (HC) and one Alzheimer's disease (AD) PET studies of both [18F]THK5351 and [11C]PIB were performed using a Eminence STARGATE scanner (Shimadzu Inc., Kyoto, Japan). All PET images were corrected for PVE by MG, GTM, Labbé (LABBE), Regional voxel-based (RBV), and Iterative Yang (IY) methods, with segmented or parcellated anatomical information processed by FreeSurfer, derived from individual MR images. PVC results of 5 algorithms were compared with the uncorrected data. RESULTS: In regions of high uptake of [18F]THK5351 and [11C]PIB, different PVCs demonstrated different SUVRs. The degree of difference between PVE uncorrected and corrected depends on not only PVC algorithm but also type of tracer and subject condition. CONCLUSION: Presented PVC methods are straight-forward to implement but the corrected images require careful interpretation as different methods result in different levels of recovery.

Glucose Metabolic Changes in the Brain and Muscles of Patients with Nonspecific Neck Pain Treated by Spinal Manipulation Therapy: A [18F]FDG PET Study.

Objective. The aim of this study was to investigate changes in brain and muscle glucose metabolism that are not yet known, using positron emission tomography with [18F]fluorodeoxyglucose ([18F]FDG PET). Methods. Twenty-one male volunteers were recruited for the present study. [18F]FDG PET scanning was performed twice on each subject: once after the spinal manipulation therapy (SMT) intervention (treatment condition) and once after resting (control condition). We performed the SMT intervention using an adjustment device. Glucose metabolism of the brain and skeletal muscles was measured and compared between the two conditions. In addition, we measured salivary amylase level as an index of autonomic nervous system (ANS) activity, as well as muscle tension and subjective pain intensity in each subject. Results. Changes in brain activity after SMT included activation of the dorsal anterior cingulate cortex, cerebellar vermis, and somatosensory association cortex and deactivation of the prefrontal cortex and temporal sites. Glucose uptake in skeletal muscles showed a trend toward decreased metabolism after SMT, although the difference was not significant. Other measurements indicated relaxation of cervical muscle tension, decrease in salivary amylase level (suppression of sympathetic nerve activity), and pain relief after SMT. Conclusion. Brain processing after SMT may lead to physiological relaxation via a decrease in sympathetic nerve activity.

In vivo visualization of tau deposits in corticobasal syndrome by 18F-THK5351 PET.

OBJECTIVE: To determine whether 18F-THK5351 PET can be used to visualize tau deposits in brain lesions in live patients with corticobasal syndrome (CBS). METHODS: We evaluated the in vitro binding of 3H-THK5351 in postmortem brain tissues from a patient with corticobasal degeneration (CBD). In clinical PET studies, 18F-THK5351 retention in 5 patients with CBS was compared to that in 8 age-matched normal controls and 8 patients with Alzheimer disease (AD). RESULTS: 3H-THK5351 was able to bind to tau deposits in the postmortem brain with CBD. In clinical PET studies, the 5 patients with CBS showed significantly higher 18F-THK5351 retention in the frontal, parietal, and globus pallidus than the 8 age-matched normal controls and patients with AD. Higher 18F-THK5351 retention was observed contralaterally to the side associated with greater cortical dysfunction and parkinsonism. CONCLUSIONS: 18F-THK5351 PET demonstrated high tracer signal in sites susceptible to tau deposition in patients with CBS. 18F-THK5351 should be considered as a promising candidate radiotracer for the in vivo imaging of tau deposits in CBS.

Brain Metabolic Changes of Cervical Dystonia with Spinocerebellar Ataxia Type 1 after Botulinum Toxin Therapy.

We occasionally observe long-term remission of cervical dystonia after several botulinum toxin treatments. However, botulinum toxin transiently acts on neuromuscular junctions. We herein report that a cervical dystonia patient with spinocerebellar ataxia type 1 could have long-term remission as a result of the depression of hypermetabolism in the bilateral putamen and primary sensorimotor cortex after botulinum toxin therapy. We suggest that botulinum toxin impacts the central nervous system, causing prolonged improvement through the normalization of basal ganglia circuits in addition to its effects at neuromuscular junctions.

Dynamic PET Measures of Tau Accumulation in Cognitively Normal Older Adults and Alzheimer's Disease Patients Measured Using [18F] THK-5351.

BACKGROUND: [18F]THK5351, a recently-developed positron emission tomography (PET) tracer for measuring tau neurofibrillary tangle accumulation, may help researchers examine aging, disease, and tau pathology in living human brains. We examined THK5351 tracer pharmacokinetics to define an optimal acquisition time for static late images. METHODS: Primary measurements were calculation of regional values of distribution volume ratios (DVR) and standardized uptake value ratios (SUVR) in 6 healthy older control and 10 Alzheimer's disease (AD) participants. We examined associations between DVR and SUVR, searching for a 20 min SUVR time window that was stable and comparable to DVR. We additionally examined diagnostic group differences in this 20 min SUVR. RESULTS: In healthy controls, [18F]THK5351 uptake was low, with increased temporal relative to frontal binding. In AD, regional uptake was substantially higher than in healthy controls, with temporal exceeding frontal binding. Retention in cerebellar gray matter, which was used as the reference region, was low compared to other regions. Both DVR and SUVR values showed minimal change over time after 40 min. SUVR 20-40, 30-50, and 40-60 min were most consistently correlated with DVR; SUVR 40-60 min, the most stable time window, was used in further analyses. Significant (AD > healthy control) group differences existed in temporoparietal regions, with marginal medial temporal differences. We found high basal ganglia SUVR 40-60 min signal, with no group differences. CONCLUSIONS: We examined THK5351, a new PET tracer for measuring tau accumulation, and compared multiple analysis methods for quantifying regional tracer uptake. SUVR 40-60 min performed optimally when examining 20 min SUVR windows, and appears to be a practical method for quantifying relative regional tracer retention. The results of this study offer clinical potential, given the usefulness of THK5351-PET as a biomarker of tau pathology in aging and disease.

18F-THK5351: A Novel PET Radiotracer for Imaging Neurofibrillary Pathology in Alzheimer Disease.

UNLABELLED: Imaging of neurofibrillary pathology in the brain helps in diagnosing dementia, tracking disease progression, and evaluating the therapeutic efficacy of antidementia drugs. The radiotracers used in this imaging must be highly sensitive and specific for tau protein fibrils in the human brain. We developed a novel tau PET tracer, (18)F-THK5351, through compound optimization of arylquinoline derivatives. METHODS: The in vitro binding properties, pharmacokinetics, and safety of (18)F-THK5351 were investigated, and a clinical study on Alzheimer disease (AD) patients was performed. RESULTS: (18)F-THK5351 demonstrated higher binding affinity for hippocampal homogenates from AD brains and faster dissociation from white-matter tissue than did (18)F-THK5117. The THK5351 binding amount correlated with the amount of tau deposits in human brain samples. Autoradiography of brain sections revealed that THK5351 bound to neurofibrillary tangles selectively and with a higher signal-to-background ratio than did THK5117. THK5351 exhibited favorable pharmacokinetics and no defluorination in mice. In first-in-human PET studies in AD patients, (18)F-THK5351 demonstrated faster kinetics, higher contrast, and lower retention in subcortical white matter than(18)F-THK5117. CONCLUSION: (18)F-THK5351 is a useful PET tracer for the early detection of neurofibrillary pathology in AD patients.

Longitudinal Assessment of Tau Pathology in Patients with Alzheimer's Disease Using [18F]THK-5117 Positron Emission Tomography.

The formation of neurofibrillary tangles is believed to contribute to the neurodegeneration observed in Alzheimer's disease (AD). Postmortem studies have shown strong associations between the neurofibrillary pathology and both neuronal loss and the severity of cognitive impairment. However, the temporal changes in the neurofibrillary pathology and its association with the progression of the disease are not well understood. Tau positron emission tomography (PET) imaging is expected to be useful for the longitudinal assessment of neurofibrillary pathology in the living brain. Here, we performed a longitudinal PET study using the tau-selective PET tracer [18F]THK-5117 in patients with AD and in healthy control subjects. Annual changes in [18F]THK-5117 binding were significantly elevated in the middle and inferior temporal gyri and in the fusiform gyrus of patients with AD. Compared to patients with mild AD, patients with moderate AD showed greater changes in the tau load that were more widely distributed across the cortical regions. Furthermore, a significant correlation was observed between the annual changes in cognitive decline and regional [18F]THK-5117 binding. These results suggest that the cognitive decline observed in patients with AD is attributable to the progression of neurofibrillary pathology. Longitudinal assessment of tau pathology will contribute to the assessment of disease progression and treatment efficacy.