Jae Yong Choi

In vivo cortical spreading pattern of tau and amyloid in the Alzheimer disease spectrum

To determine the in vivo cortical spreading pattern of tau and amyloid and to establish positron emission tomography (PET) image‐based tau staging in the Alzheimer disease (AD) spectrum.

Tau PET in Alzheimer disease and mild cognitive impairment.

Objective: To investigate the topographical distribution of tau pathology and its effect on functional and structural changes in patients with Alzheimer disease (AD) and mild cognitive impairment (MCI) by using 18F-AV-1451 PET. Methods: We included 20 patients with AD, 15 patients with MCI, and 20 healthy controls, and performed neuropsychological function tests, MRI, as well as 18F-florbetaben (for amyloid) and 18F-AV-1451 (for tau) PET scans. By using the regional volume-of-interest masks extracted from MRIs, regional binding values of standardized uptake value ratios and volumes were measured. We compared regional binding values among 3 diagnostic groups and identified correlations among the regional binding values, performance in each cognitive function test, and regional atrophy. Results: 18F-AV-1451 binding was increased only in the entorhinal cortex in patients with MCI, while patients with AD exhibited greater binding in most cortical regions. In the 35 patients with MCI and AD, 18F-AV-1451 binding in most of the neocortex increased with a worsening of global cognitive function. The visual and verbal memory functions were associated with the extent of 18F-AV-1451 binding, especially in the medial temporal regions. The 18F-AV-1451 binding also correlated with the severity of regional atrophy of the cerebral cortex. Conclusions: Tau PET imaging with 18F-AV-1451 could serve as an in vivo biomarker for the evaluation of AD-related tau pathology and monitoring disease progression. The accumulation of pathologic tau is more closely related to functional and structural deterioration in the AD spectrum than β-amyloid.

Subcortical 18F-AV-1451 binding patterns in progressive supranuclear palsy

Accumulation of cortical and subcortical tau pathology is the primary pathological substrate for progressive supranuclear palsy (PSP). 18F‐AV‐1451, a radiotracer that binds to the pathological tau protein, may be helpful for in vivo visualization and quantitation of tau pathology in PSP.

Off-Target 18F-AV-1451 Binding in the Basal Ganglia Correlates with Age-Related Iron Accumulation

Off-target binding in the basal ganglia is commonly observed in the 18F-AV-1451 PET studies of the elderly. We sought to investigate the relationship between this phenomenon in the basal ganglia and iron accumulation using iron-sensitive R2* MRI. Methods: Fifty-nine healthy controls and 61 patients with Alzheimer disease and mild cognitive impairment underwent 18F-AV-1451 PET and R2* MRI studies. A correlation analysis was performed for age, 18F-AV-1451 binding, and R2* values. Results: There was an age-related increase in both 18F-AV-1451 binding in the basal ganglia and R2* values in the putamen in both the controls and the Alzheimer disease/mild cognitive impairment patients. 18F-AV-1451 binding in the basal ganglia increased with R2* values. Conclusion: Off-target 18F-AV-1451 binding in the basal ganglia is associated with the age-related increases in iron accumulation. Postmortem studies are required to further investigate the nature of this association.

Effective microPET imaging of brain 5-HT(1A) receptors in rats with [(18) F]MeFWAY by suppression of radioligand defluorination.

Introduction: [18F]MeFWAY has been developed for imaging the serotonin 1A receptors in the brain. The purpose of this study were to verify the metabolic stability of [18F]MeFWAY, to measure the degree of defluorination of [18F]MeFWAY in vivo, to investigate methods of inhibition of defluorination of [18F]MeFWAY, and to assess the efficacy of [18F]MeFWAY in rat brains in vivo. Methods: MicroPET experiments in rats were conducted to confirm the distribution of radioactivity in the brain. Nondisplaceable binding potential (BPND) in the hippocampus and frontal cortex were also analyzed. Miconazole and fluconazole were tested for the ability to suppress defluorination of [18F]MeFWAY. We conducted a blockade and displacement experiment by treating with WAY‐100635. Results: In vitro stability tests showed that MeFWAY was very stable in serum for 6 h, but PET revealed that authentic [18F]MeFWAY underwent significant defluorination in vivo. In vitro inhibition study against decreasing parent activity in liver microsomes, miconazole and fluconazole suppressed metabolic elimination of MeFWAY. However, in the PET study, fluconazole showed more potent inhibitory activity than miconazole. In the suppression of metabolizing enzymes using fluconazole, radioactivity in skull was dramatically decreased by 81% (compared with 69% with miconazole) and it was coupled with an increase in brain uptake. Moreover, BPND in hippocampus was 5.53 and 2.66 in frontal cortex. The blockade and displacement study showed the specificity of [18F]MeFWAY to 5‐HT1A receptors. Conclusion: In the rat brain, [18F]MeFWAY microPET showed skull uptake due to defluorination in vivo. We can effectively overcome this drawback with fluconazole. Synapse, 2012.

Excessive tau accumulation in the parieto-occipital cortex characterizes early-onset Alzheimer's disease

Early-onset Alzheimers disease (EOAD) is characterized by greater nonmemory dysfunctions, more rapid progression, and greater hypometabolism and atrophy than late-onset AD (LOAD). We sought to investigate the differences in tau accumulation patterns between early- and late-onset patients with AD and mild cognitive impairment (MCI). In 90 patients who completed 18F-AV-1451 and 18F-florbetaben positron emission tomography scans, only 59 amyloid-positive patients (11 EOAD, 10 EOMCI, 21 LOAD, and 17 LOMCI) were included in this study. We compared cortical 18F-AV-1451 binding between each patient group and corresponding amyloid-negative age-matched controls. In contrast to no difference in cortical binding between the EOMCI and LOMCI groups, EOAD showed greater binding in the parieto-occipital cortex than LOAD. The parieto-occipital binding correlated with visuospatial dysfunction in the EOAD spectrum, whereas binding in the temporal cortex correlated with verbal memory dysfunction in the LOAD spectrum. Our findings suggest that distinct topographic distribution of tau may influence the nature of cognitive impairment in EOAD patients.

Relationship between dopamine deficit and the expression of depressive behavior resulted from alteration of serotonin system

Depression frequently accompanies in Parkinsons disease (PD). Previous research suggested that dopamine (DA) and serotonin systems are closely linked with depression in PD. However, comprehensive studies about the relationship between these two neurotransmitter systems are limited. Therefore, the purpose of this study is to evaluate the effect of dopaminergic destruction on the serotonin system. The interconnection between motor and depression was also examined. Two PET scans were performed in the 6‐hydroxydopamine (6‐OHDA) lesioned and sham operated rats: [18F]FP‐CIT for DA transporters and [18F]Mefway for serotonin 1A (5‐HT1A) receptors. Here, 6‐OHDA is a neurotoxin for dopaminergic neurons. Behavioral tests were used to evaluate the severity of symptoms: rotational number for motor impairment and immobility time, acquired from the forced swim test for depression. Region‐of‐interests were drawn in the striatum and cerebellum for the DA system and hippocampus and cerebellum for the 5‐HT system. The cerebellum was chosen as a reference region. Nondisplaceable binding potential in the striatum and hippocampus were compared between 6‐OHDA and sham groups. As a result, the degree of DA depletion was negatively correlated with rotational behavior (R2 = 0.79, P = 0.003). In 6‐OHDA lesioned rats, binding values for 5‐HT1A receptors was 22% lower than the sham operated group. This decrement of 5‐HT1A receptor binding was also correlated with the severity of depression (R2 = 0.81, P = 0.006). Taken together, this research demonstrated that the destruction of dopaminergic system causes the reduction of the serotonergic system resulting in the expression of depressive behavior. The degree of dopaminergic dysfunction was positively correlated with the impairment of the serotonin system. Severity of motor symptoms was also closely related to depressive behavior. Synapse 69:453–460, 2015.

18F‐AV‐1451 binds to putamen in multiple system atrophy

MSA is a synucleinopathy. It may exhibit a binding pattern similar to that expected for Parkinson’s disease (PD) in the PET studies with F-AV-1451, a recently developed radiotracer specific for pathological tau protein. Contrary to our expectations, we report on 4 consecutive probable parkinsonian-type MSA patients in whom increased F-AV1451 binding was detected in the atrophic putamen. Nigrostriatal dopaminergic deficit was confirmed by the FN-3-fluoropropyl-2-betacarboxymethoxy-3-beta-(4-iodophenyl) nortropane (FP-CIT) PET scan in all 4 patients, who underwent F-AV-1451 PET scans. Subcortical binding patterns in these patients were compared with that of 30 healthy controls. This study was approved by the institutional review board of Gangnam Severance Hospital (Seoul, Republic of Korea), and written informed consent was obtained from all participants. All 4 MSA patients showed volume atrophy and reduced F-FP-CIT uptake in the putamen, which clearly mirrored increased F-AV-1451 binding in the posterior putamen (Fig. 1A–C). When compared to the mean standard uptake value ratio (SUVR) values of controls, 3 patients (patients 2–4) showed greater F-AV-1451 binding in the posterior FIG. 1. A: Native [18F]-AV-1451 PET scan showing an axial view of the basal ganglia. B: T1 weighted MRI showing an axial view of the midbrain. C/D: Axial and midsagittal view of z-transformed deviations of [18F]-AV-1451 uptake from a norm cohort.

Evaluation of dopamine transporters and D2 receptors in hemiparkinsonian rat brains in vivo using consecutive PET scans of [18F]FPCIT and [18F]fallypride.

The aim of this study was to investigate dopaminergic function in unilaterally lesioned 6-OHDA rats by dual PET radioligands: [(18)F]FPCIT (a dopamine transporter imaging radioligand) and [(18)F]fallypride (a dopamine D2 receptors imaging radioligand). As a result, the brain uptake of [(18)F]FPCIT was significantly reduced and that of [(18)F]fallypride was increased in the ipsilateral striatum (lesion side) of the 6-OHDA rats. These findings implicated that dopamine transporter is down-regulated and dopamine D2 receptor is up-regulated in this hemiparkinsonian rat model.

Environmental enrichment enhances synaptic plasticity by internalization of striatal dopamine transporters

Environmental enrichment (EE) with a complex combination of physical, cognitive and social stimulations enhances synaptic plasticity and behavioral function. However, the mechanism remains to be elucidated in detail. We aimed to investigate dopamine-related synaptic plasticity underlying functional improvement after EE. For this, six-week-old CD-1 mice were randomly allocated to EE or standard conditions for two months. EE significantly enhanced behavioral functions such as rotarod and ladder walking tests. In a [18F]FPCIT positron emission tomography scan, binding values of striatal DAT were significantly decreased approximately 18% in the EE mice relative to the control mice. DAT inhibitor administrated to establish the relationship of the DAT down-regulation to the treatment effects also improved rotarod performances, suggesting that DAT inhibition recapitulated EE-mediated treatment benefits. Next, EE-induced internalization of DAT was confirmed using a surface biotinylation assay. In situ proximity ligation assay and immunoprecipitation demonstrated that EE significantly increased the phosphorylation of striatal DAT as well as the levels of DAT bound with protein kinase C (PKC). In conclusion, we suggest that EE enables phosphorylation of striatal DAT via a PKC-mediated pathway and causes DAT internalization. This is the first report to suggest an EE-mediated mechanism of synaptic plasticity by internalization of striatal DAT.