Imaging of amyloid deposition in human brain using positron emission tomography and [18F]FACT: comparison with [11C]PIB.

PURPOSE: The characteristic neuropathological changes in Alzheimer's disease (AD) are deposition of amyloid senile plaques and neurofibrillary tangles. The (18)F-labeled amyloid tracer, [(18)F]2-[(2-{(E)-2-[2-(dimethylamino)-1,3-thiazol-5-yl]vinyl}-1,3-benzoxazol-6-yl)oxy]-3-fluoropropan-1-ol (FACT), one of the benzoxazole derivatives, was recently developed. In the present study, deposition of amyloid senile plaques was measured by positron emission tomography (PET) with both [(11)C]Pittsburgh compound B (PIB) and [(18)F]FACT in the same subjects, and the regional uptakes of both radiotracers were directly compared. METHODS: Two PET scans, one of each with [(11)C]PIB and [(18)F]FACT, were performed sequentially on six normal control subjects, two mild cognitive impairment (MCI) patients, and six AD patients. The standardized uptake value ratio of brain regions to the cerebellum was calculated with partial volume correction using magnetic resonance (MR) images to remove the effects of white matter accumulation. RESULTS: No significant differences in the cerebral cortical uptake were observed between normal control subjects and AD patients in [(18)F]FACT studies without partial volume correction, while significant differences were observed in [(11)C]PIB. After partial volume correction, the cerebral cortical uptake was significantly larger in AD patients than in normal control subjects for [(18)F]FACT studies as well as [(11)C]PIB. Relatively lower uptakes of [(11)C]PIB in distribution were observed in the medial side of the temporal cortex and in the occipital cortex as compared with [(18)F]FACT. Relatively higher uptake of [(11)C]PIB in distribution was observed in the frontal and parietal cortices. CONCLUSION: Since [(18)F]FACT might bind more preferentially to dense-cored amyloid deposition, regional differences in cerebral cortical uptake between [(11)C]PIB and [(18)F]FACT might be due to differences in regional distribution between diffuse and dense-cored amyloid plaque shown in the autoradiographic and histochemical assays of postmortem AD brain sections.

ß-Amyloid in Lewy body disease is related to Alzheimer's disease-like atrophy.

The aim of this study was to investigate whether amyloid deposition is associated with Alzheimer's disease (AD)-like cortical atrophy in Lewy body (LB) disease (LBD). Participants included 15 LBD with dementia patients (8 with dementia with Lewy bodies [DLB] and 7 with Parkinson's disease [PD] with dementia [PDD]), 13 AD patients, and 17 healthy controls. Age, gender, and Mini-Mental State Examination scores were matched between patient groups. All subjects underwent PET scans with [(11)C]Pittsburgh Compound B to measure brain amyloid deposition as well as three-dimensional T1-weighted MRI. Gray-matter volumes (GMVs) were estimated by voxel-based morphometry. Volumes-of-interest analyses were also performed. Forty percent of the 15 DLB/PDD patients were amyloid positive, whereas all AD patients and none of the healthy controls were amyloid positive. Amyloid-positive DLB/PDD and AD patients showed very similar patterns of cortical atrophy in the parahippocampal area and lateral temporal and parietal cortices, with 95.2% of cortical atrophy distribution being overlapped. In contrast, amyloid-negative DLB/PDD patients had no significant cortical atrophy. Compared to healthy controls, parahippocampal GMVs were reduced by 26% in both the amyloid-positive DLB/PDD and AD groups and by 10% in the amyloid-negative DLB/PDD group. The results suggest that amyloid deposition is associated with AD-like atrophy in DLB/PDD patients. Early intervention against amyloid may prevent or delay AD-like atrophy in DLB/PDD patients with amyloid deposition.

Effect of risperidone on high-affinity state of dopamine D2 receptors: a PET study with agonist ligand [11C](R)-2-CH3O-N-n-propylnorapomorphine.

The increased proportion of the high-affinity state of dopamine D2/3 receptors (D2,high) is assumed to correlate with dopamine hypersensitivity, implying a relationship with psychotic symptoms observed in psychiatric disorders such as schizophrenia. [11C](R)-2-CH3O-N-n-propylnorapomorphine ([11C]MNPA), which has an agonistic property to dopamine D2 receptors (D2Rs), is expected to bind preferentially to D2,high. The occupancy of dopamine D2Rs by antagonists to receptors has not been investigated using [11C]MNPA. We compared dopamine D2R occupancies by risperidone, an antagonist to receptors, between [11C]MNPA and [11C]raclopride to confirm whether risperidone occupies D2,high and D2,low at almost identical proportions. PET studies were performed on 11 healthy men under resting condition and following oral administration of a single dose of risperidone (0.5-2.0 mg). Striatal receptor occupancy for each radioligand was calculated. The relationship between dose or plasma concentration of risperidone and dopamine D2R occupancy was calculated. Striatal dopamine D2R occupancies measured with [11C]MNPA and [11C]raclopride were 22-65% and 24-69%, respectively. In the striatum, ED50 values measured with [11C]MNPA and [11C]raclopride were 0.98 and 1.03 mg, respectively. The striatal ED50 values as calculated from plasma concentration were 9.15 ng/ml and 8.01 ng/ml, respectively. Almost identical occupancies and ED50 values were observed between the two radioligands, indicating that risperidone bound to D2,high and D2,low at almost identical proportions in a dose-dependent manner.

Effects of the antipsychotic risperidone on dopamine synthesis in human brain measured by positron emission tomography with L-[beta-11C]DOPA: a stabilizing effect for dopaminergic neurotransmission?

Effects of antipsychotic drugs have widely been considered to be mediated by blockade of postsynaptic dopamine D(2) receptors. Effects of antipsychotics on presynaptic functions of dopaminergic neurotransmission might also be related to therapeutic effects of antipsychotics. To investigate the effects of antipsychotics on presynaptic functions of dopaminergic neurotransmission in relation with occupancy of dopamine D(2) receptors, changes in dopamine synthesis capacity by antipsychotics and occupancy of dopamine D(2) receptors were measured by positron emission tomography (PET) in healthy men. PET studies using [(11)C]raclopride and L-[beta-(11)C]DOPA were performed under resting condition and oral administration of single dose of the antipsychotic drug risperidone on separate days. Although occupancy of dopamine D(2) receptors corresponding dose of risperidone was observed, the changes in dopamine synthesis capacity by the administration of risperidone were not significant, nor was the relation between the occupancy of dopamine D(2) receptors and these changes. A significant negative correlation was observed between the baseline dopamine synthesis capacity and the changes in dopamine synthesis capacity by risperidone, indicating that this antipsychotic can be assumed to stabilize the dopamine synthesis capacity. The therapeutic effects of risperidone in schizophrenia might be related to such stabilizing effects on dopaminergic neurotransmission responsivity.

Quantitative analysis of peripheral benzodiazepine receptor in the human brain using PET with (11)C-AC-5216.

UNLABELLED: Peripheral benzodiazepine receptor (PBR) is upregulated in activated glial cells and is therefore a useful biomarker for inflammation in the brain and neurodegenerative disorders. We developed a new PET radioligand, (11)C-AC-N-benzyl-N-ethyl-2-(7-methyl-8-oxo-2-pheyl-7,8-dihydro-9H-purin-9-yl)acetamide ((11)C-AC-5216), that allows the imaging and quantification of PBRs in monkey and mouse brains. The aim of this study was to evaluate a quantification method of (11)C-AC-5216 binding in the human brain. METHODS: A 90-min dynamic PET scan was obtained for each of 12 healthy men after an intravenous injection of (11)C-AC-5216. Regions of interest were drawn on several brain regions. Binding potential, compared with nondisplaceable uptake (BP(ND)), was calculated by a nonlinear least-squares fitting (NLS) method with the 2-tissue-compartment model, and total volume of distribution (V(T)) was estimated by NLS and graphical analysis methods. RESULTS: BP(ND) was highest in the thalamus (4.6 +/- 1.0) and lowest in the striatum (3.5 +/- 0.7). V(T) obtained by NLS or graphical analysis showed regional distribution similar to BP(ND). However, there was no correlation between BP(ND) and V(T) because of the interindividual variation of K(1)/k(2). BP(ND) obtained with data from a scan time of 60 min was in good agreement with that from a scan time of 90 min (r = 0.87). CONCLUSION: Regional distribution of (11)C-AC-5216 was in good agreement with previous PET studies of PBRs in the human brain. BP(ND) is more appropriate for estimating (11)C-AC-5216 binding than is V(T) because of the interindividual variation of K(1)/k(2). (11)C-AC-5216 is a promising PET ligand for quantifying PBR in the human brain.

Quantitative PET analysis of the dopamine D2 receptor agonist radioligand 11C-(R)-2-CH3O-N-n-propylnorapomorphine in the human brain.

UNLABELLED: It has been demonstrated in vitro that the dopamine D(2) receptor has 2 interconvertible affinity states for endogenous dopamine, referred to as the high- and the low-affinity states. (11)C-(R)-2-CH(3)O-N-n-propylnorapomorphine ((11)C-MNPA) is a new agonist radioligand for in vivo imaging of the high-affinity state of dopamine D(2) receptors using PET. In the present study, the kinetics of (11)C-MNPA were examined for the first time, to our knowledge, in the human brain and analyzed using quantitative approaches with or without an arterial input function. METHODS: A 90-min dynamic PET scan was obtained for 10 healthy men after an intravenous injection of (11)C-MNPA. The binding potential (BP(ND)) was calculated using the indirect kinetic method, a kinetic compartment analysis with a metabolite-corrected arterial input function. BP(ND) was also calculated by the simplified reference tissue model (SRTM) and transient equilibrium methods, both with the cerebellum as the reference brain region. The results of the quantitative methods were compared in a cross-validation approach. RESULTS: The highest regional radioactivity was observed in the putamen. BP(ND) values obtained by kinetic analysis were 0.82 +/- 0.09, 0.59 +/- 0.11, and 0.28 +/- 0.06, respectively, in the putamen, caudate, and thalamus. BP(ND) values obtained by the SRTM and transient equilibrium methods were in good agreement with those obtained by the indirect kinetic method (r = 0.98 and r = 0.93, respectively). For all quantification methods, the BP(ND) values based on data acquired from 0 to 60 min were in good agreement with those based on data acquired from 0 to 90 min (r = 0.90-0.99). CONCLUSION: The regional distribution of (11)C-MNPA binding was in good agreement with previous PET studies of dopamine D(2) receptors in the human brain using antagonist radioligands. The results support routine use of the SRTM and transient equilibrium methods, that is, methods that do not require an arterial input function and need a scan time of only about 60 min. (11)C-MNPA should thus be useful for clinical research on the pathophysiology of neuropsychiatric disorders and estimation of dopamine D(2) receptor occupancy by dopaminergic drugs.

Neuroimaging in dementia: in vivo amyloid imaging.

Dementia, a progressive cognitive decline, leads to a gradually increasing restriction of daily activities. Alzheimer's disease (AD) is the most common form of dementia. The pathological features of AD include plaques and tangles which are constituted by amyloid beta peptide (A beta) and tau protein. These amyloidogenic molecules have been mechanistically implicated in the pathogenesis of AD and related neurodegenerative dementias. The key strategy for establishment of diagnostic and therapeutic approaches to AD is sensitive and specific detection of the incipient neuropathology characteristics of AD, combined with emerging treatments that counteract molecular processes in AD pathogenesis. Recent advances in molecular imaging research have enabled visualization of brain amyloidosis. The rapid development of different compounds suitable for visualizing amyloid would permit pathology-specific diagnosis of AD at an asymptomatic stage in a noninvasive manner, and could also allow early immunotherapeutic intervention without causing an excessive neuroinflammatory response.

[Distribution and function of dopamine D1, D2 receptor].

Positron emission tomography (PET) techniques have made it possible to measure changes in target molecular in living human brain. PET can be used to investigate various brain functions such as receptors, transporters, enzymes and various biochemical pathways; therefore, it could be a powerful tool for molecular imaging of functional neurotransmission. Since dopamine is an important molecule for pathophysiology of Parkinson's disease and schizophrenia, we reviewed in vivo imaging studies focusing on dopaminergic transmission. Dopamine D2 receptor occupancy by antipsychotics and it's time-course have been measured using PET. This approach can provide in vivo pharmacological evidences of antipsychotics and establish the rational therapeutic strategy. PET is a powerful tool not only in the field of brain research but also drug discovery. On the other hand Dopamine D1 receptor is highly expressed in the prefrontal cortex, has been implicated in the control of working memory, seeking, craving, reward. We propose that dysfunction of Dopamine D1 receptor signalling in the prefrontal cortex may contribute to the negative symptoms and cognitive deficits seen in schizophrenia and we suggest that Dopamine D1 receptor binding and cerebral blood flow changes in ventral striatum play the important role of cigarette craving.

Estimation of plasma IC50 of donepezil for cerebral acetylcholinesterase inhibition in patients with Alzheimer disease using positron emission tomography.

OBJECTIVES: Estimate the value of in vivo plasma IC50 of donepezil, the concentration of donepezil in plasma that inhibits brain acetylcholinesterase (AChE) activity by 50% at the steady-state conditions of donepezil between the plasma and the brain. METHODS: N-[C] methylpiperidin-4-yl acetate ([C]MP4A) positron emission tomography was performed in 16 patients with probable Alzheimer disease (AD) before and during the treatment of donepezil (5 mg/day) with a mean interval of 5.3 months. The plasma IC50 value of donepezil was estimated from plasma donepezil concentrations and cerebral cortical mean AChE inhibition rates measured by positron emission tomography, using one-parameter model. RESULTS: Donepezil reduced AChE activity uniformly in the cerebral cortex compared with the baseline in each AD patient, and the mean reduction rate in the cerebral cortex was 34.6%. The donepezil concentrations in the plasma ranged from 18.5 to 43.9 ng/mL with a mean of 28.9 +/- 7.3 ng/mL. The plasma IC50 value was estimated to be 53.6 +/- 4.0 ng/mL. CONCLUSIONS: Once the plasma IC50 of donepezil is determined, the brain AChE inhibition rate could be estimated from the plasma concentration of donepezil in each subject based on the plasma IC50. Now that the mean donepezil concentrations in the plasma, when the patients took 5 mg/day, remained 28.9 ng/mL, approximately half of the plasma IC50, higher dose of donepezil might provide further benefits for patients with AD. This technique can be also applied to measure the in vivo plasma IC50 of other cholinesterase inhibitors such as rivastigmine and galantamine.

In vivo detection of neuropathologic changes in presymptomatic MAPT mutation carriers: a PET and MRI study.

BACKGROUND: Microglial activation and disrupted neurotransmissions may herald symptomatic manifestations in neurodegenerative tauopathies. METHODS: We investigated microglial activation with [(11)C]DAA1106 positron emission tomography (PET), striatal dopaminergic function with l-[beta-(11)C]dopa PET, acetylcholinesterase (AChE) activity with [(11)C]N-methylpiperidin-4-yl acetate PET, and morphologic brain changes with MRI in three persons (aged 38-41 years) with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), who were presymptomatic gene carriers (PGCs) from an American kindred with pallidopontonigral degeneration. The results from these 3 PGCs were compared with [(11)C]DAA1106 PET results from age-matched 9 healthy volunteers (HV), and with l-[beta-(11)C]dopa and [(11)C]MP4A PET results from 10 HV. Values considered significant were more than 2 SDs greater or less than the normal control mean, as the number of subjects was small for group comparisons. RESULTS: Glial activities were increased in the frontal cortex of one PGC, the occipital cortex of two PGCs, and the posterior cingulate cortex of one PGC, although none of the PGCs showed overt glial activation in the brain. Only one of the PGCs showed reduced AChE activity in the temporo-parietal cortex. Three PGCs showed low dopamine synthesis rates in the putamen. Hippocampal atrophy was observed in two PGCs. CONCLUSIONS: Hippocampal atrophy and striatal dopaminergic dysfunction may be early disease processes in the pathogenesis of FTDP-17. Neuroinflammation may also be an in vivo signature of tau pathology at a prodromal stage, although current PET techniques may not constantly reveal it as the earliest neuroimaging abnormality.