Synaptic Density and Glucose Consumption in Patients with Lewy Body Diseases: An [11C]UCB-J and [18F]FDG PET Study

Background

Patients with Lewy body diseases exhibit variable degrees of cortical and subcortical hypometabolism. However, the underlying causes behind this progressive hypometabolism remain unresolved. Generalized synaptic degeneration may be one key contributor.

Objective

The objective of this study was to investigate whether local cortical synaptic loss is proportionally linked to the magnitude of hypometabolism in Lewy body disease.

Method

Using in vivo positron emission tomography (PET) we investigated cerebral glucose metabolism and quantified the density of cerebral synapses, as measured with [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) PET and [¹¹C]UCB-J, respectively. Volumes-of-interest were defined on magnetic resonance T1 scans and regional standard uptake value ratios-1 values were obtained for 14 pre-selected brain regions. Between-group comparisons were conducted at voxel-level.

Results

We observed regional differences in both synaptic density and cerebral glucose consumption in our cohorts of non-demented and demented patients with Parkinson's disease or dementia with Lewy bodies compared to healthy subjects. Additionally, voxel-wise comparisons showed a clear difference in cortical regions between demented patients and controls for both tracers. Importantly, our findings strongly suggested that the magnitude of reduced glucose uptake exceeded the magnitude of reduced cortical synaptic density.

Conclusion

Here, we investigated the relationship between in vivo glucose uptake and the magnitude of synaptic density as measured using [¹⁸F]FDG PET and [¹¹C]UCB-J PET in Lewy body patients. The magnitude of reduced [¹⁸F]FDG uptake was greater than the corresponding decline in [¹¹C]UCB-J binding. Therefore, the progressive hypometabolism seen in Lewy body disorders cannot be fully explained by generalized synaptic degeneration. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Evaluation of [18F]-JNJ-64326067-AAA tau PET tracer in humans

The [¹⁸F]-JNJ-64326067-AAA ([¹⁸F]-JNJ-067) tau tracer was evaluated in healthy older controls (HCs), mild cognitive impairment (MCI), Alzheimer’s disease (AD), and progressive supranuclear palsy (PSP) participants. Seventeen subjects (4 HCs, 5 MCIs, 5 ADs, and 3 PSPs) received a [¹¹C]-PIB amyloid PET scan, and a tau [¹⁸F]-JNJ-067 PET scan 0-90 minutes post-injection. Only MCIs and ADs were amyloid positive. The simplified reference tissue model, Logan graphical analysis distribution volume ratio, and SUVR were evaluated for quantification. The [¹⁸F]-JNJ-067 tau signal relative to the reference region continued to increase to 90 min, indicating the tracer had not reached steady state. There was no significant difference in any bilateral ROIs for MCIs or PSPs relative to HCs; AD participants showed elevated tracer relative to controls in most cortical ROIs (P < 0.05). Only AD participants showed elevated retention in the entorhinal cortex. There was off-target signal in the putamen, pallidum, thalamus, midbrain, superior cerebellar gray, and white matter. [¹⁸F]-JNJ-067 significantly correlated (p < 0.05) with Mini-Mental State Exam in entorhinal cortex and temporal meta regions. There is clear binding of [¹⁸F]-JNJ-067 in AD participants. Lack of binding in HCs, MCIs and PSPs suggests [¹⁸F]-JNJ-067 may not bind to low levels of AD-related tau or 4 R tau.     

Head‐to‐head comparison of 18F‐FP‐CIT and 123I‐FP‐CIT for dopamine transporter imaging in patients with Parkinson's disease: A preliminary study

¹²³I‐FP‐CIT and ¹⁸F‐FP‐CIT are radiotracers which are widely used to diagnose Parkinson's disease (PD). However, to our knowledge, no studies to date have made head‐to‐head comparisons between ¹²³I‐FP‐CIT and ¹⁸F‐FP‐CIT. Therefore, in this study, ¹²³I‐FP‐CIT SPECT/CT was compared with ¹⁸F‐FP‐CIT PET/CT in the same cohort of subjects. Patients with PD and essential tremor (ET) underwent ¹²³I‐FP‐CIT SPECT/CT and ¹⁸F‐FP‐CIT PET/CT. Visual and semiquantitative analyses were conducted. The specific binding ratio (SBR) and putamen to caudate ratio (PCR) were compared between subjects who underwent ¹²³I‐FP‐CIT SPECT/CT and ¹⁸F‐FP‐CIT PET/CT. Visual analysis showed that the striatal uptake of both radiotracers was decreased in the PD group, whereas striatal uptake was intact in the ET group. The SBR between ¹²³I‐FP‐CIT SPECT/CT and ¹⁸F‐FP‐CIT PET/CT showed a positive correlation (r = .78, p < .01). However, the mean SBRs on ¹⁸F‐FP‐CIT PET/CT were higher than those on ¹²³I‐FP‐CIT SPECT/CT (2.19 ± .87 and 1.22 ± .49, respectively; p < .01). The PCRs in these two modalities were correlated with each other (r = .71, p < .01). The mean PCRs on ¹⁸F‐FP‐CIT PET/CT were not significantly higher than those on ¹²³I‐FP‐CIT SPECT/CT (1.31 ± .19 and 0.98 ± .06, respectively; p = .06). These preliminary results indicate that the uptake of both ¹²³I‐FP‐CIT and ¹⁸F‐FP‐CIT was decreased in the PD group when compared with the ET controls. Visual analyses using both methods did not affect the diagnostic accuracy in this study. However, semiquantitative analysis indicated a better contrast of ¹⁸F‐FP‐CIT PET/CT relative to ¹²³I‐FP‐CIT SPECT/CT.     

Comparison of [11C]UCB-J and [18F]FDG PET in Alzheimer’s disease: A tracer kinetic modeling study

[¹¹C]UCB-J PET for synaptic vesicle glycoprotein 2 A (SV2A) has been proposed as a suitable marker for synaptic density in Alzheimer’s disease (AD). We compared [¹¹C]UCB-J binding for synaptic density and [¹⁸F]FDG uptake for metabolism (correlated with neuronal activity) in 14 AD and 11 cognitively normal (CN) participants. We assessed both absolute and relative outcome measures in brain regions of interest, i.e., K₁ or R₁ for [¹¹C]UCB-J perfusion, V_T (volume of distribution) or DVR to cerebellum for [¹¹C]UCB-J binding to SV2A; and K_i or K_iR to cerebellum for [¹⁸F]FDG metabolism. [¹¹C]UCB-J binding and [¹⁸F]FDG metabolism showed a similar magnitude of reduction in the medial temporal lobe of AD –compared to CN participants. However, the magnitude of reduction of [¹¹C]UCB-J binding in neocortical regions was less than that observed with [¹⁸F]FDG metabolism. Inter-tracer correlations were also higher in the medial temporal regions between synaptic density and metabolism, with lower correlations in neocortical regions. [¹¹C]UCB-J perfusion showed a similar pattern to [¹⁸F]FDG metabolism, with high inter-tracer regional correlations. In summary, we conducted the first in vivo PET imaging of synaptic density and metabolism in the same AD participants and reported a concordant reduction in medial temporal regions but a discordant reduction in neocortical regions.     

Direct comparison of [18F]MH.MZ and [18F]altanserin for 5‐HT2A receptor imaging with PET

Imaging the cerebral serotonin 2A (5‐HT_2A) receptors with positron emission tomography (PET) has been carried out in humans with [¹¹C]MDL 100907 and [¹⁸F]altanserin. Recently, the MDL 100907 analogue [¹⁸F]MH.MZ was developed combining the selectivity profile of MDL 100907 and the favourable radiophysical properties of fluorine‐18. Here, we present a direct comparison of [¹⁸F]altanserin and [¹⁸F]MH.MZ. 5‐HT_2A receptor binding in pig cortex and cerebellum was investigated by autoradiography with [³H]MDL 100907, [¹⁸F]MH.MZ, and [¹⁸F]altanserin. [¹⁸F]MH.MZ and [¹⁸F]altanserin were investigated in Danish Landrace pigs by brain PET scanning at baseline and after i.v. administration of blocking doses of ketanserin. Full arterial input function and high performance liquid chromatography (HPLC) analysis allowed for tissue‐compartment kinetic modeling of PET data. In vitro autoradiography showed high binding in cortical regions with both [¹⁸F]MH.MZ and [¹⁸F]altanserin. Significant 5‐HT_2A receptor binding was also found in the pig cerebellum, thus making this region unsuitable as a reference region for in vivo data analysis in this species. The cortical binding of [¹⁸F]MH.MZ and [¹⁸F]altanserin was blocked by ketanserin supporting that both radioligands bind to 5‐HT_2A receptors in the pig brain. In the HPLC analysis of pig plasma, [¹⁸F]MH.MZ displayed a fast and reproducible metabolism resulting in hydrophilic radiometabolites only whereas the metabolic profile of [¹⁸F]altanserin as expected showed lipophilic radiometabolites. Due to the slow kinetics of [¹⁸F]MH.MZ in high‐binding regions in vivo, we suggest that [¹⁸F]MH.MZ will be an appropriate tracer for low binding regions where kinetics will be faster, whereas [¹⁸F]altanserin is a suitable tracer for high‐binding regions. Synapse, 2013. © 2013 Wiley Periodicals, Inc.     

Striatal and extrastriatal dopamine release measured with PET and [18F] fallypride

The amphetamine challenge, in which positron emission tomography (PET) or single photon emission computed tomography radioligand binding following administration of amphetamine is compared to baseline values, has been successfully used in a number of brain imaging studies as an indicator of dopaminergic function, particularly in the striatum. [¹⁸F] fallypride is the first PET radioligand that allows measurement of the effects of amphetamine on D2/D3 ligand binding in striatum and extra‐striatal brain regions in a single scanning session following amphetamine. We scanned 15 healthy volunteer subjects with [¹⁸F] fallypride at baseline and following amphetamine (0.3 mg/kg) using arterial plasma input‐based modeling as well as reference region methods. We found that amphetamine effect was robustly detected in ventral striatum, globus pallidus, and posterior putamen, and with slightly higher variability in other striatal subregions. However, the observed effect sizes in striatum were less than those observed in previous studies in our laboratory using [¹¹C] raclopride. Robust effect was also detected in limbic extra‐striatal regions (hippocampus, amygdala) and substantia nigra, but the signal‐to‐noise ratio was too low to allow accurate measurement in cortical regions. We conclude that [¹⁸F] fallypride is a suitable ligand for measuring amphetamine effect in striatum and limbic regions, but it is not suitable for measuring the effect in cortical regions and may not provide the most powerful way to measure the effect in striatum. Synapse 64:350–362, 2010. © 2009 Wiley‐Liss, Inc.     

The auditory startle response in parkinsonism may reveal the extent but not type of pathology

OBJECTIVES: We measured the acoustic startle response (ASR) and blink reflex (ABR) in patients with clinically diagnosed Parkinson's disease (PD) and progressive supranuclear palsy (PSP) and determined the specificity of an abnormal result for the diagnosis of PSP. METHODS: Thirty patients (11 PD, 19 PSP) and 12 age matched controls were studied. The PSP group was separated into clinical subgroups. Fourteen patients with early falls, cognitive dysfunction and eye movement abnormalities were classified as Richardson's disease (RD), 3 with parkinsonism in the absence of early falls, cognitive dysfunction or eye movement abnormalities were classified PSP-parkinsonism (PSP-P) and 2 who presented with gait unsteadiness and freezing without cognitive dysfunction or eye movement abnormalities were classified as pure akinesia with gait freezing (PAGF). Following an acoustic startle stimulus EMG activity was recorded in the orbicularis oculi and sternomastoid muscles. The likelihood ratio of an absent response being clinically diagnosed PSP was determined. RESULTS: The ABR was present in 11/19 (58%) of patients with PSP, and 11/11 with PD and 12/12 controls (H2 p < 0.05). The ASR measured at the sternomastoid was present in only 2/19 (11%) of patients with PSP, but in 5/11 (45%) with PD and 6/12 (50 %) controls (H2 p < 0.05). The ABR was present in only 6/14 (43%) of the RD group, but in 3/3 PSP-P and 2/2 PAGF. Loss of the ABR was 100% specific for PSP, but only 42 % sensitive. Loss of the sternomastoid ASR had a likelihood ratio of 1.9 for the clinical diagnosis of PSP. CONCLUSIONS: The ASR and ABR appear unlikely to be useful in differentiating PSP from PD.Abnormalities in these responses are worse in RD where the pathology is known to be more widespread than in PSP-P and PAGF.     

[C]PIB-, [F]FDG-PET and MRI imaging in patients with Parkinson’s disease with and without dementia

The objective of this study was to identify possible group differences between PD patients with dementia and without dementia by combining different functional and structural imaging methods in vivo, which might provide an opportunity to disentangle the pathophysiological correlates of cognitive impairment and dementia in PD. We performed a neuropsychological evaluation, structural brain MRI, [¹⁸F]FDG PET and [¹¹C]PIB PET in 19 PD patients [eight non-demented (PD), eleven demented (PDD)] and 24 healthy elderly volunteers. [¹¹C]PIB region-to-cerebellum ratios did not differ significantly between the groups in any brain region (p > 0.05). PDD patients showed impaired glucose metabolism in cortical brain regions and this reduction was associated with the degree of cognitive impairment. PDD patients had more atrophy both in the hippocampus and the frontal cortex compared with PD patients and controls, and hippocampal atrophy was associated with impaired memory. This cross-sectional data suggests that development of dementia in PD is associated with extensive spread of hypometabolism beyond the occipital cortex, and with hippocampal and frontal atrophy but not beta-amyloid deposition consistent with a unique biological process related to PD rather than co-incidental development of AD in persons with PD.     

Increased microglial activation in patients with Parkinson disease using [18F]-DPA714 TSPO PET imaging

IntroductionIncreasing evidence suggests that neuroinflammation is active in Parkinson disease (PD) and contributes to neurodegeneration. This process can be studied in vivo with PET and radioligands targeting TSPO, upregulated in activated microglia. Initial PET studies investigating microglial activation in PD with the [¹¹C]-PK11195 have provided inconclusive results. Here we assess the presence and distribution of neuroinflammatory response in PD patients using [¹⁸F]-DPA714 and to correlate imaging biomarkers to dopamine transporter imaging and clinical status.MethodsPD patients (n = 24, Hoehn and Yahr I-III) and 28 healthy controls were scanned with [¹⁸F]-DPA714 and [¹¹C]-PE2I and analyzed. They were all genotyped for TSPO polymorphism. Regional binding parameters were estimated (reference Logan graphical approach with supervised cluster analysis). Impact of TSPO genotype was analyzed using Wilcoxon signed-rank test. Differences between groups were investigated using a two-way ANOVA and Tukey post hoc tests.ResultsPD patients showed significantly higher [¹⁸F]-DPA714 binding compared to healthy controls bilaterally in the midbrain (p < 0.001), the frontal cortex (p = 0.001), and the putamen contralateral to the more clinically affected hemibody (p = 0.038). Microglial activation in these regions did not correlate with the severity of motor symptoms, disease duration nor putaminal [¹¹C]-PE2I uptake. However, there was a trend toward a correlation between cortical TSPO binding and disease duration (p = 0.015 uncorrected, p = 0.07 after Bonferroni correction).Conclusion[¹⁸F]-DPA714 binding confirmed that there is a specific topographic pattern of microglial activation in the nigro-striatal pathway and the frontal cortex of PD patients.Trial registrationTrial registration: INFLAPARK, NCT02319382. Registered 18 December 2014- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02319382.     

18F-FCWAY and 18F-FDG PET in MRI-negative temporal lobe epilepsy

Background: Positron emission tomography (PET) with ¹⁸F‐fluorodeoxyglucose (FDG) shows widespread hypometabolism even in temporal lobe epilepsy (TLE) patients with mesial temporal foci. ¹⁸F‐trans‐4‐fluoro‐N‐2‐[4‐(2‐methoxyphenyl) piperazin‐1‐yl]ethyl‐N‐(2‐pyridyl)cyclohexane carboxamide (¹⁸F‐FCWAY) PET may show more specific 5‐HT_1A‐receptor binding reduction in seizure initiation than in propagation regions. ¹⁸FCWAY PET might be valuable for detecting epileptic foci, and distinguishing mesial from lateral temporal foci in MRI‐negative patients with TLE. Methods: We performed ¹⁸F‐FCWAY‐PET and ¹⁸F‐FDG‐PET in 12 MRI‐negative TLE patients who had had either surgery or subdural electrode recording, and 15 healthy volunteers. After partial volume correction for brain atrophy, free fraction‐corrected volume of distribution (V/f1) measurement and asymmetry indices (AIs) were computed. We compared ¹⁸F‐FCWAY‐PET and ¹⁸F‐FDG‐PET results with scalp video electroencephalography (EEG), invasive EEG, and surgical outcome. Results: Mean ¹⁸F‐FCWAY V/f1, compared with normal controls, was decreased significantly in fusiform gyrus, hippocampus, and parahippocampus ipsilateral to epileptic foci, and AIs were significantly greater in hippocampus, parahippocampus, fusiform gyrus, amygdala, and inferior temporal regions. Eleven patients had clearly lateralized epileptogenic zones. Nine had congruent, and two nonlateralized, ¹⁸F‐FCWAY PET. One patient with bitemporal seizure onset had nonlateralized ¹⁸F‐FCWAY‐PET. ¹⁸F‐FDG‐PET showed congruent hypometabolism in 7 of 11 EEG‐lateralized patients, bilateral hypometabolic regions in one, contralateral hypometabolism in one, as well as lateralized hypometabolism in the patient with bitemporal subdural seizure onset. Patients with mesial temporal foci tended to have lower superior and midtemporal ¹⁸F‐FCWAY V/f1 binding AI than those with lateral or diffuse foci. Conclusion: ¹⁸F‐FCWAY‐PET can detect reduced binding in patients with normal MRI, and may be more accurate than ¹⁸F‐FDG‐PET.     

In vitro autoradiography and in vivo evaluation in cynomolgus monkey of [18F]FE‐PE2I,a new dopamine transporter PET radioligand

This study evaluated the in vitro and in vivo characteristics of a new dopamine transporter (DAT) radioligand, [¹⁸F]fluoroethyl(FE)PE2I, by autoradiography from postmortem human brain and by positron emission tomography (PET) in three cynomolgus monkeys. In the autoradiography experiments, high [¹⁸F]FE‐PE2I accumulation was observed in caudate and putamen that was selectively abolished by GBR12909 or β‐CIT but not by maprotiline. High doses of citalopram (>5 μM) also inhibited [¹⁸F]FE‐PE2I binding in the striatum. In vitro K_i of the radioligand was 12 nM at rodent dopamine transporter. [¹⁸F]FE‐PE2I brain uptake measured by PET was ～4–5% of the injected dose, with highest uptake in striatum followed by midbrain and thalamus, lower uptake in neocortex, and lowest in cerebellum. Peak specific binding in striatum was reached ～40 min and in midbrain 20–30 min postinjection. The ratio‐to‐cerebellum was 7–10 in striatum and 1.5–2.3 in midbrain. BP_ND measured with simplified reference tissue method using the cerebellum as reference region was 4.5 in striatum and 0.6 in midbrain. No displacement was shown after citalopram or maprotiline administration, while GBR12909 decreased the binding in striatum and midbrain to the level of cerebellum. [¹⁸F]FE‐PE2I showed relatively fast elimination and metabolism with the presence of two metabolite peaks with similar retention time as the labeled metabolites of [¹¹C]PE2I. [¹⁸F]FE‐PE2I showed in vivo selectivity for the DAT and compared with [¹¹C]PE2I, it showed faster kinetics and earlier peak equilibrium. The potential influence of the two radiometabolites on PET quantification requires further evaluation. Synapse 63:871–880, 2009. © 2009 Wiley‐Liss, Inc.     

Glucose metabolism in sporadic Creutzfeldt-Jakob disease: a statistical parametric mapping analysis of (18) F-FDG PET

Background and purpose: Reports describing functional neuroimaging techniques, such as positron emission tomography (PET) and single‐photon emission computed tomography (SPECT), in sporadic Creutzfeldt–Jakob disease (sCJD) have consistently suggested that these tools are sensitive for the identification of areas of hypoperfusion or hypometabolism, even in the early stages of sCJD. However, there are few reports on the use of [18F]fluoro‐2‐deoxy‐D‐glucose (FDG) PET in sCJD, and most of them are single case reports. Only two small cohort studies based on visual inspection or a region of interest method have been published to date. Using a statistical parametric mapping (SPM) analysis of ¹⁸F‐FDG PET, we investigated whether there are brain regions preferentially affected in sCJD. Methods: After controlling for age and gender, using SPM 2, we compared the glucose metabolism between (i) 11 patients with sCJD and 35 controls and (ii) the subset of five patients with the Heidenhain variant of sCJD and 35 controls. Results: The patients with sCJD showed decreased glucose metabolism in bilateral parietal, frontal and occipital cortices. The Heidenhain variant of sCJD showed glucose hypometabolism mainly in bilateral occipital areas. Conclusions: Glucose hypometabolism in sCJD was detected in extensive cortical regions; however, it was not found in the basal ganglia or thalamus, which are frequently reported to be affected on diffusion‐weighted images. The medial temporal area, which is possibly resistant to the prion deposits, was also less involved in sCJD.     

Activation of NMDA receptor ion channels by deep brain stimulation in the pig visualised with [18F]GE-179 PET

BackgroundNo PET radioligand has yet demonstrated the capacity to map glutamate N-methyl-d-aspartate receptor ion channel (NMDAR-IC) function. [¹⁸F]GE-179 binds to the phencyclidine (PCP) site in open NMDAR-ICs and potentially provides a use-dependent PET biomarker of these ion channels.ObjectiveTo show [¹⁸F]GE-179 PET can detect increased NMDAR-IC activation during electrical deep brain stimulation (DBS) of pig hippocampus.MethodsSix minipigs had an electrode implanted into their right hippocampus. They then had a baseline [¹⁸F]GE-179 PET scan with DBS turned off followed by a second scan with DBS turned on. Brain [¹⁸F]GE-179 uptake at baseline and then during DBS was measured with PET. Cerebral blood flow (CBF) was measured with [¹⁵O]H₂O PET at baseline and during DBS and parametric CBF images were generated to evaluate DBS induced CBF changes. Functional effects of injecting the PCP blocker MK-801 were also evaluated. Electrode positions were later histologically verified.ResultsDBS induced a 47.75% global increase in brain [¹⁸F]GE-179 uptake (p = 0.048) compared to baseline. Global CBF was unchanged by hippocampal DBS. [¹⁸F]GE-179 PET detected a 5% higher uptake in the implanted compared with the non-implanted temporo-parietal cortex at baseline (p = 0.012) and during stimulation (p = 0.022). Administration of MK-801 before DBS failed to block [¹⁸F]GE-179 uptake during stimulation.ConclusionPET detected an increase in global brain [¹⁸F]GE-179 uptake during unilateral hippocampal DBS while CBF remained unchanged. These findings support that [¹⁸F]GE-179 PET provides a use-dependent marker of abnormal NMDAR-IC activation.     

Progression of dopaminergic hypofunction in striatal subregions in Parkinson's disease using [18F]CFT PET

The aim of this study was to investigate the progression of dopaminergic hypofunction in striatal subregions in Parkinson's disease (PD). We studied 12 patients with early PD and 11 healthy controls with a dopamine transporter ligand 2beta-carbomethoxy-3beta-(4-[(18)F]-fluorophenyl)tropane ([(18)F]CFT) positron emission tomography (PET). The PET scan was carried out twice with an average interval of 2.2 years. The regions of interest (anterior and posterior putamen, caudate nucleus, and cerebellum) were drawn on individual magnetic resonance imaging (MRI) images, matched with the PET images, and copied onto the PET images. At the first PET scan in PD patients, the [(18)F]CFT uptake in the anterior putamen was 1.92 +/- 0.67, which was 45% of the control mean, and in the posterior putamen 1.02 +/- 0.55, being only 27% of the control mean. For the caudate nucleus the corresponding figure was 2.55 +/- 0.58 (71% of the control mean). The uptake ratios had declined significantly by the time of the second PET scan and the absolute annual rate of decline of the tracer uptake was 0.23 +/- 0.14 (P < 0.001) in the anterior putamen, 0.13 +/- 0.13 (P = 0.005) in the posterior putamen, and 0.20 +/- 0.15 (P < 0.001) in the caudate nucleus. There was a statistically significant difference of the decline in the tracer uptake between the anterior and posterior putamen (P = 0.033). When the rate of progression was calculated compared to the normal control mean, the rate of annual decline was 5.3% in the anterior putamen, 3.3% in the posterior putamen, and 5.6% in the caudate nucleus, without significant changes among striatal subregions (P = 0.10). When ipsi- and contralateral sides were analyzed separately, the absolute decline of [(18)F]CFT uptake in the putamen was higher in the side ipsilateral to the predominant symptoms than in the contralateral side (P = 0.035 for anterior putamen and P = 0.026 for posterior putamen). In the caudate nucleus the absolute decline was not different between ipsi- and contralateral sides (P = 0.76). In healthy controls, no significant decline of [(18)F]CFT uptake was detected. The results are suggestive of slower progression in the posterior putamen, where the disease is more advanced, but studies to follow up the same patient at several time points are needed to resolve this question. Synapse 48:109-115, 2003.     

In-vivo measurement of LDOPA uptake,dopamine reserve and turnover in the rat brain using [18F]FDOPA PET

Longitudinal measurements of dopamine (DA) uptake and turnover in transgenic rodents may be critical when developing disease-modifying therapies for Parkinson''s disease (PD). We demonstrate methodology for such measurements using [¹⁸F]fluoro-3,4-dihydroxyphenyl-L-alanine ([¹⁸F]FDOPA) positron emission tomography (PET). The method was applied to 6-hydroxydopamine lesioned rats, providing the first PET-derived estimates of DA turnover for this species. Control (n=4) and unilaterally lesioned (n=11) rats were imaged multiple times. Kinetic modeling was performed using extended Patlak, incorporating a k_loss term for metabolite washout, and modified Logan methods. Dopaminergic terminal loss was measured via [¹¹C]-(+)-dihydrotetrabenazine (DTBZ) PET. Clear striatal [¹⁸F]FDOPA uptake was observed. In the lesioned striatum the effective DA turnover increased, shown by a reduced effective distribution volume ratio (EDVR) for [¹⁸F]FDOPA. Effective distribution volume ratio correlated (r>0.9) with the [¹¹C]DTBZ binding potential (BP_ND). The uptake and trapping rate (k_ref) decreased after lesioning, but relatively less so than [¹¹C]DTBZ BP_ND. For normal controls, striatal estimates were k_ref=0.037±0.005 per minute, EDVR=1.07±0.22 and k_loss=0.024±0.003 per minute (30 minutes turnover half-time), with repeatability (coefficient of variation) ≤11%. [¹⁸F]fluoro-3,4-dihydroxyphenyl-L-alanine PET enables measurements of DA turnover in the rat, which is useful for developing novel therapies for PD.     

Gray matter correlates of dopaminergic degeneration in Parkinson's disease: A hybrid PET/MR study using 18F‐FP‐CIT

Dopaminergic degeneration is a hallmark of Parkinson's disease (PD), which causes various symptoms affected by corticostriatal circuits. So far, the relationship between cortical changes and dopamine loss in the striatum is unclear. Here, we evaluate the gray matter (GM) changes in accordance with striatal dopaminergic degeneration in PD using hybrid PET/MR. Sixteen patients with idiopathic PD underwent ¹⁸F‐FP‐CIT PET/MR. To measure dopaminergic degeneration in PD, binding ratio (BR) of dopamine transporter in striatum was evaluated by ¹⁸F‐FP‐CIT. Voxel‐based morphometry (VBM) was used to evaluate GM density. We obtained voxelwise correlation maps of GM density according to the striatal BR. Voxel‐by‐voxel correlation between BR maps and GM density maps was done to evaluate region‐specific correlation of striatal dopaminergic degeneration. There was a trend of positive correlation between striatal BR and GM density in the cerebellum, parahippocampal gyri, and frontal cortex. A trend of negative correlation between striatal BR and GM density in the medial occipital cortex was found. Voxel‐by‐voxel correlation revealed that the positive correlation was mainly dependent on anterior striatal BR, while posterior striatal BR mostly showed negative correlation with GM density in occipital and temporal cortices. Decreased GM density related to anterior striatal dopaminergic degeneration might demonstrate degeneration of dopaminergic nonmotor circuits. Furthermore, the negative correlation could be related to the motor circuits of posterior striatum. Our integrated PET/MR study suggests that the widespread structural progressive changes in PD could denote the cortical functional correlates of the degeneration of striatal dopaminergic circuits. Hum Brain Mapp 37:1710–1721, 2016. © 2016 Wiley Periodicals, Inc .     

Reproducible network and regional topographies of abnormal glucose metabolism associated with progressive supranuclear palsy: Multivariate and univariate analyses in American and Chinese patient cohorts

Progressive supranuclear palsy (PSP) is a rare movement disorder and often difficult to distinguish clinically from Parkinson's disease (PD) and multiple system atrophy (MSA) in early phases. In this study, we report reproducible disease‐related topographies of brain network and regional glucose metabolism associated with PSP in clinically‐confirmed independent cohorts of PSP, MSA, and PD patients and healthy controls in the USA and China. Using ¹⁸F‐FDG PET images from PSP and healthy subjects, we applied spatial covariance analysis with bootstrapping to identify a PSP‐related pattern (PSPRP) and estimate its reliability, and evaluated the ability of network scores for differential diagnosis. We also detected regional metabolic differences using statistical parametric mapping analysis. We produced a highly reliable PSPRP characterized by relative metabolic decreases in the middle prefrontal cortex/cingulate, ventrolateral prefrontal cortex, striatum, thalamus and midbrain, covarying with relative metabolic increases in the hippocampus, insula and parieto‐temporal regions. PSPRP network scores correlated positively with PSP duration and accurately discriminated between healthy, PSP, MSA and PD groups in two separate cohorts of parkinsonian patients at both early and advanced stages. Moreover, PSP patients shared many overlapping areas with abnormal metabolism in the same cortical and subcortical regions as in the PSPRP. With rigorous cross‐validation, this study demonstrated highly comparable and reproducible PSP‐related metabolic topographies at network and regional levels across different patient populations and PET scanners. Metabolic brain network activity may serve as a reliable and objective marker of PSP, although cross‐validation applying recent diagnostic criteria and classification is warranted.     

Evidence for modulation of opioidergic activity in central vestibular processing: A [18F] diprenorphine PET study

Animal and functional imaging studies had identified cortical structures such as the parieto‐insular vestibular cortex, the retro‐insular cortex, or the anterior cingulate cortex belonging to a vestibular cortical network. Basic animal studies revealed that endorphins might be important transmitters involved in cerebral vestibular processing. The aim of the present study was therefore to analyse whether the opioid system is involved in vestibular neurotransmission of humans or not. Changes in opioid receptor availability during caloric air stimulation of the right ear were studied with [¹⁸F] Fluoroethyl‐diprenorphine ([¹⁸F]FEDPN) PET scans in 10 right‐handed healthy volunteers and compared to a control condition. Decrease in receptor availability to [¹⁸F]FEDPN during vestibular stimulation in comparison to the control condition was significant at the right posterior insular cortex and the postcentral region indicating more endogenous opioidergic binding in these regions during stimulation. These data give evidence that the opioidergic system plays a role in the right hemispheric dominance of the vestibular cortical system in right‐handers. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.     

Endogenous competition against binding of [18F]DMFP and [18F]fallypride to dopamine D2/3 receptors in brain of living mouse

Aim . Molecular imaging studies with benzamide radioligands can reveal competition from endogenous binding at D_2/3‐receptors in living brain. However, single photon emission computed tomography (SPECT) methods suffer from limited spatial resolution, and [¹¹C]‐labeled ligands are only available at positron emission tomography (PET) research sites with cyclotron‐radiochemistry facilities, whereas [¹⁸F] can be transported, due to its longer physical half‐life. Therefore, we endeavored to characterize the vulnerabilities of the benzamide antagonist [¹⁸F]desmethoxyfallypride (DMFP) and its high‐affinity congener [¹⁸F]fallypride (FP) to competition from endogenous dopamine in living mouse brain. Methods . Groups of awake mice were pretreated with saline, amphetamine (10 mg/kg), or reserpine (5 mg/kg), followed by i.v. tracer injections. Mice were killed at 2.5–90 min (DMFP) or 2.5–180 min (FP) circulation times. Brains were dissected and regional radioactivity concentration measured by gamma counting. Other groups of mice were anesthetized for dynamic microPET recordings with DMFP or FP. Binding potentials (BP_ND) were calculated using cerebellum as reference region. Results . With 90‐min circulation, DMFP BP_ND in striatum was 2.4 by dissection and 2.2 by microPET, which showed a 62% decrease in response to amphetamine‐evoked dopamine release and a 33% increase after reserpine‐evoked dopamine depletion. With 120‐min circulation, FP BP_ND in striatum was 24.1 by dissection and 9.2 by microPET, which showed a 31% decrease in the amphetamine group, but no effect of reserpine. Dissection showed similar sensitivities for FP binding, but only a 29% amphetamine‐evoked reduction for DMFP. Conclusions . Relative to gold standard ex vivo results, microPET estimates of DMFP BP_ND were unbiased, whereas FP BP_ND in striatum was substantially underestimated. Both tracers proved suitable for revealing pharmacologically evoked changes in competition at D_2/3‐receptors in striatum of living mice. Synapse 64:313–322, 2010. © 2009 Wiley‐Liss, Inc.     

Disparity of perfusion and glucose metabolism of epileptogenic zones in temporal lobe epilepsy demonstrated by SPM/SPAM analysis on 15O water PET, [18F]FDG-PET, and [99mTc]-HMPAO SPECT

PURPOSE: To elucidate uncoupling of perfusion and metabolism and its significance in epilepsy, 15O water and 18F fluorodeoxyglucose (FDG) positron emission tomography (PET) and Tc-99m hexamethyl-propyleneamine-oxime (HMPAO) single-photon emission computed tomography (SPECT) were examined by SPM (statistical parametric mapping) and quantitation by using SPAM (statistical probabilistic anatomic map). METHODS: [15O]water and [18F]FDG-PET, and [99mTc]-HMPAO SPECT were performed in 25 patients (SPECT in 17 of 25) with medial temporal lobe epilepsy. For volume of interest (VOI) count analysis, the normalized counts using VOI based on SPAM templates of PET and SPECT were compared with those of the normal controls. Perfusion or metabolism was found abnormal if the Z score was >2 for each VOI. For SPM analysis, the differences between each patient's image and a group of normal control images (t statistic for p < 0.01) on a voxel-by-voxel basis were examined to find significant decreases in perfusion or metabolism. RESULTS: With SPAM VOI count analysis, areas of hypoperfusion were found in 13 patients in the epileptogenic temporal lobes by [15O]water PET and areas of hypometabolism in 21 patients by [18F]FDG-PET. With voxel-based SPM analysis, the epileptogenic zones were localized in 15 by [15O]water PET and in 23 patients by [18F]FDG-PET. The localization by [15O]water PET was concordant with that of [18F]FDG-PET. The areas of hypoperfusion on [15O]water PET were absent or smaller than the areas of hypometabolism on [18F]FDG-PET. Interictal [99mTc]-HMPAO SPECT revealed the hypoperfused zones in seven of 17 patients on visual assessment. CONCLUSIONS: SPAM VOI count and SPM analysis of [15O]water and [18F]FDG-PET and [99mTc]-HMPAO SPECT revealed that in the same patients, the areas of hypoperfusion were concordant with but smaller than the areas of hypometabolism. Discordance of perfusion and metabolic abnormalities represents an uncoupling of perfusion and metabolism in the epileptogenic zones, and this might explain the lower diagnostic accuracy of perfusion imaging in temporal lobe epilepsy.