Masamichi Yokokura

Neuroinflammation in the living brain of Parkinson's disease.

Evidence shows that neuronal injury accompanies neuroinflammatory reactions in the brain, and well as in Parkinsons disease (PD) animal models, in which the loss of dopamine neurons is associated with the activation of microglia in the substantia nigra. Activated microglia can be illustrated in vivo using Positron emission tomography and [(11)C](R)-PK11195. However, this tracer cannot distinguish between the two aspects of microglial function (protective and inflammatory). To solve this problem, we can use a dopamine transporter marker, [(11)C]CFT, which binds to the dopamine transporter. The binding of the tracer reflects the viability of the presynaptic dopaminergic neurons, as reported in a multicenter trial using single photon emission tomography (SPECT) with [(123I)]beta-CIT, a SPECT version of [(11)C]CFT. In early drug-naïve PD patients, these two tracers showed a unique pattern of binding, [(11)C](R)-PK11195 binding potential in the midbrain was correlated inversely with [(11)C]CFT binding in the putamen, and midbrain [(11)C](R)-PK11195 binding was found to be positively correlated with the motor severity of parkinsonism. These results indicate that early introduction of a neuroprotective drug to suppress microglial activation is favorable in PD and that [(11)C](R)-PK11195 can be used to monitor the progression of the disease. As the disease progressed, the [(11)C]CFT binding was further decreased, and the microglial activation spread over the entire brain. This paper briefly summarizes the neuroinflammation induced by microglia in PD and describes an in vivo aspect of the neuroinflammation in the PD brain by focusing on the covarying changes in microglial activation and neuronal damage.

In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer’s disease

PurposeAmyloid β protein (Aβ) is known as a pathological substance in Alzheimer’s disease (AD) and is assumed to coexist with a degree of activated microglia in the brain. However, it remains unclear whether these two events occur in parallel with characteristic hypometabolism in AD in vivo. The purpose of the present study was to clarify the in vivo relationship between Aβ accumulation and neuroinflammation in those specific brain regions in early AD.MethodsEleven nootropic drug-naïve AD patients underwent a series of positron emission tomography (PET) measurements with [11C](R)PK11195, [11C]PIB and [18F]FDG and a battery of cognitive tests within the same day. The binding potentials (BPs) of [11C](R)PK11195 were directly compared with those of [11C]PIB in the brain regions with reduced glucose metabolism.ResultsBPs of [11C](R)PK11195 and [11C]PIB were significantly higher in the parietotemporal regions of AD patients than in ten healthy controls. In AD patients, there was a negative correlation between dementia score and [11C](R)PK11195 BPs, but not [11C]PIB, in the limbic, precuneus and prefrontal regions. Direct comparisons showed a significant negative correlation between [11C](R)PK11195 and [11C]PIB BPs in the posterior cingulate cortex (PCC) (p < 0.05, corrected) that manifested the most severe reduction in [18F]FDG uptake.ConclusionA lack of coupling between microglial activation and amyloid deposits may indicate that Aβ accumulation shown by [11C]PIB is not always the primary cause of microglial activation, but rather the negative correlation present in the PCC suggests that microglia can show higher activation during the production of Aβ in early AD.

Amygdala kindling induces upregulation of mRNA for NKCC1, a Na+, K+–2Cl− cotransporter, in the rat piriform cortex

GABA, the main inhibitory neurotransmitter in the brain, elicits a hyperpolarizing response by activation of the GABA(A)-receptor/chloride-channel complex under conditions of normal Cl(-) homeostasis. Thus the pathogenesis of epilepsy could involve an impairment of GABA(A)-receptor-mediated inhibition due to a collapse of the Cl(-) gradient. We examined the expression patterns of Cl(-) transporters and a Cl(-) channel in a rat amygdala-kindling model. Activity-dependent increases were observed in the mRNA for NKCC1, an inwardly-directed Cl(-) transporter, in the piriform cortex. This suggests that an increase in [Cl(-)](i) and a resultant reduction in GABAergic inhibition may occur in the kindled piriform cortex.

Changes in chloride homeostasis-regulating gene expressions in the rat hippocampus following amygdala kindling

In a rat kindling model, we examined expression patterns of NKCC1, KCC1, KCC2, and CLC-2. In the dentate granule cell layer, there was an activity-dependent increase in NKCC1 mRNA but significant decreases in KCC1 and CLC-2 mRNAs. In addition, CLC-2 mRNA expression was markedly decreased in CA1 pyramidal layer. These results suggest that an increase in [Cl-]i and a resultant reduction in GABAergic inhibition may occur in hippocampus of epileptic rats.

Progression from Unilateral to Bilateral Parkinsonism in Early Parkinson Disease: Implication of Mesocortical Dopamine Dysfunction by PET

It is still unclear why some early Parkinson disease (PD) patients with unilateral parkinsonism develop bilateral parkinsonism soon after the diagnosis is made as Hoehn and Yahr (HY) stage 1 and others remain stable for a long time. Here, we examined in vivo changes in the brain dopaminergic system using PET with a dopamine transporter radiotracer, 11C-2-B-carbomethoxy-3B-(4-fluorophenyl) tropane (11C-CFT), to elucidate the pathophysiologic characteristics of the dopamine system in early converters. Methods: Twelve drug-naïve PD patients with HY stage 1 disease and 8 age-matched healthy subjects participated in this study. Clinical evaluation of their parkinsonism was performed monthly until their HY stage 1 (unilateral parkinsonism) disease had become stage 2 (bilateral parkinsonism) disease according to the Unified Parkinson Disease Rating Scale. The endpoint of the follow-up study was the time of the conversion. Region-of-interest analysis was used to examine 11C-CFT binding in the mesocortical (nucleus accumbens, caudate, orbitofrontal cortex) and nigrostriatal (putamen) dopamine projection regions. Multiregression analyses between these PET data and clinical parameters were performed within the PD group. Results: Between-group comparisons showed that, irrespective of the duration of conversion, all PD patients clinically diagnosed at HY stage 1 had a significant reduction in 11C-CFT binding in the bilateral striatum (affected, −46%; unaffected, −35%). Regression analysis showed that the level of 11C-CFT binding in the nucleus accumbens and orbitofrontal cortex on the unaffected side was significantly positively correlated with the conversion interval. This positive correlation indicates that the more severe a dysfunction presents in the mesocortical dopamine system on the seemingly intact side, the more rapidly the parkinsonism proceeds to the intact side (bilateral parkinsonism). Conclusion: The finding of bilateral reduction in the striatal 11C-CFT binding even in HY stage 1 PD patients confirms that molecular changes in the dopamine system precede clinical phenotype, suggesting an advantage of PET for detecting an early abnormality of the disease. The spread of parkinsonism to the unaffected side soon after the diagnosis of HY stage 1 PD may be related to the degree of mesocortical dopamine dysfunction.

Depiction of microglial activation in aging and dementia: Positron emission tomography with [11C]DPA713 versus [11C](R)PK11195

The presence of activated microglia in the brains of healthy elderly people is a matter of debate. We aimed to clarify the degree of microglial activation in aging and dementia as revealed by different tracers by comparing the binding potential (BPND) in various brain regions using a first-generation translocator protein (TSPO) tracer [11C](R)PK11195 and a second-generation tracer [11C]DPA713. The BPND levels, estimated using simplified reference tissue models, were compared among healthy young and elderly individuals and patients with Alzheimer’s disease (AD) and were correlated with clinical scores. An analysis of variance showed category-dependent elevation in levels of [11C]DPA713 BPND in all brain regions and showed a significant increase in the AD group, whereas no significant changes among groups were found when [11C](R)PK11195 BPND was used. Cognito-mnemonic scores were significantly correlated with [11C]DPA713 BPND levels in many brain regions, whereas [11C](R)PK11195 BPND failed to correlate with the scores. As mentioned elsewhere, the present results confirmed that the second-generation TSPO tracer [11C]DPA713 has a greater sensitivity to TSPO in both aging and neuronal degeneration than [11C](R)PK11195. Positron emission tomography with [11C]DPA713 is suitable for the delineation of in vivo microglial activation occurring globally over the cerebral cortex irrespective of aging and degeneration.

Effects of Brain Amyloid Deposition and Reduced Glucose Metabolism on the Default Mode of Brain Function in Normal Aging

Brain β-amyloid (Aβ) deposition during normal aging is highlighted as an initial pathogenetic event in the development of Alzheimers disease. Many recent brain imaging studies have focused on areas deactivated during cognitive tasks [the default mode network (DMN), i.e., medial frontal gyrus/anterior cingulate cortex and precuneus/posterior cingulate cortex], where the strength of functional coordination was more or less affected by cerebral Aβ deposits. In the present positron emission tomography study, to investigate whether regional glucose metabolic alterations and Aβ deposits seen in nondemented elderly human subjects (n = 22) are of pathophysiological importance in changes of brain hemodynamic coordination in DMN during normal aging, we measured cerebral glucose metabolism with [18F]FDG, Aβ deposits with [11C]PIB, and regional cerebral blood flow during control and working memory tasks by H215O on the same day. Data were analyzed using both region of interest and statistical parametric mapping. Our results indicated that the amount of Aβ deposits was negatively correlated with hemodynamic similarity between medial frontal and medial posterior regions, and the lower similarity was associated with poorer working memory performance. In contrast, brain glucose metabolism was not related to this medial hemodynamic similarity. These findings suggest that traceable Aβ deposition, but not glucose hypometabolism, in the brain plays an important role in occurrence of neuronal discoordination in DMN along with poor working memory in healthy elderly people.

A pilot study of serotonergic modulation after long‐term administration of oxytocin in autism spectrum disorder

Oxytocin (OT) and the serotonergic system putatively play important roles in autism spectrum disorder (ASD) etiology and symptoms, but no direct neurobiological evidence exists for long‐term OT administration effects on the brains serotonergic system. This pilot study examined 10 male participants with ASD who were administered OT intranasally for 8–10 weeks in an open‐label, single‐arm, nonrandomized, and uncontrolled manner. Positron emission tomography (PET) with a radiotracer (11C)−3‐amino‐4‐(2‐[(dimethylamino)methyl]phenylthio)benzonitrile (11C‐DASB) was used before and after OT treatment. The binding potential of serotonin transporter (11C‐DASB BPND) was then estimated. The main outcome measures were changes in 11C‐DASB BPND and their correlation with changes in symptoms. ASD participants showed significantly elevated 11C‐DASB BPND in the left inferior frontal gyrus extending to the left middle frontal gyrus. No significant correlation was found between the change in any clinical symptom and the change in 11C‐DASB BPND. This report of a pilot study is the first describing long‐term effects of OT on the brains serotonin system in ASD. Additional randomized controlled studies must be conducted to confirm whether activation of the serotonergic system contributes to the prosocial effect of OT in people with ASD. Autism Res 2017, 10: 821–828.

F148. A PILOT STUDY OF [11C] (R)-MEQAA PET BRAIN IMAGING ANALYSIS OF ALPHA 7 NICOTINIC ACETYLCHOLINE RECEPTORS AVAILABILITY IN SCHIZOPHRENIA

Abstract Background A growing body of evidence suggests that the aberrant cholinergic system may underlie the pathophysiology in schizophrenia. Nicotinic acetylcholine receptor (nAChR) subtype α7 (henceforth ‘α7 nAChR’) is located in presynaptic and postsynaptic constructs in the cerebral cortex and considered to play a key role in the regulation of learning and memory. Additionally, α7 nAChR is deemed to exert neuroprotective effects. Therefore, α7 nAChR is one of the potent therapeutic targets for negative symptoms and cognitive impairment in schizophrenia. In effect, several randomised trials to assess the efficacy and safety of α7 nAChR agonists are currently underway. There is some evidence in support of aberrant α7 nAChR in schizophrenia. In postmortem studies, protein levels of α7 nAChR in the frontal cortex (Guan et al., 1999) have been reported to be decreased in patients with schizophrenia. However, the availability of α7 nAChR in individuals with schizophrenia has yet to be examined in vivo. In this pilot study, we aim to clarify availability of α7 nAChR in the brains of patients with schizophrenia using positron emission tomography (PET) with a ligand of [11C](R)-2-methylamino-benzoic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester ([11C](R)-MeQAA). Methods All participants provided informed consent. Inclusion criteria included diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5, 2013). Patients were excluded if they had (1) full IQ under 69 measured with the Wechsler Adult Intelligent Scale-III; (2) current or past history of tobacco smoking; (3) history of neurological disorder or structural brain abnormality; (4) use of benzodiazepines, antidepressants, or anticholinergics in the past 6 months; and (5) substance abuse. Although scanning drug-free or drug-naïve patients for investigation is optimal, it is extremely difficult to attain this. Consequently, participants with schizophrenia comprised medicated cases. We evaluated the availability of α7 nAChR by estimating non-displaceable binding potential (BPND) of the tracer using PET with [11C] (R)-MeQAA, a selective PET tracer for α7 nAChR. Four patients with schizophrenia (age: range 27–39; m/f: 2/2) and 5 age-matched healthy adults (age: range 22–32; m/f: 2/3) underwent the PET scan. The level of BPND in patients with schizophrenia was compared with that for control participants by applying regions of interest (ROIs) approach. In this pilot study, we opted for 4 cortical areas, the superior frontal, middle frontal, parietal, and temporal cortices, for ROIs. This study was approved by the Hamamatsu University School of Medicine Ethics Committee. Results We found the levels of [11C] (R)-MeQAA BPND significantly lower in the middle frontal cortex (p = 0.036) in patients with schizophrenia. Additionally, there was a trend towards a decreased level of BPND in the temporal cortex (p = 0.067) and parietal cortex (p = 0.087) in the brains of schizophrenia patients, although it failed to reach statistical significance. There was no difference in the superior frontal cortex. Discussion To our knowledge, this represents the first demonstration of anomalies in the acetylcholinergic system in the in vivo brains of schizophrenia patients. However, this is regarded as a pilot study, and further recruitment of schizophrenia patients with a recent onset and minimal use of antipsychotic medication, followed by scanning and data analyses, will be continued.

Neuroinflammation following disease modifying therapy in multiple sclerosis: A pilot positron emission tomography study

INTRODUCTION Chronic activation of microglia accelerates the neurodegenerative process in multiple sclerosis (MS). Although disease modifying therapy (DMT) is reportedly effective for neuroinflammatory responses in MS, the progression of neuroinflammation after DMT remains unclear. METHODS We evaluated microglial activation in six clinically stable relapsing-remitting MS patients after DMT by quantifying changes in translocator protein (TSPO) density using PET with [11C]DPA713, a selective TSPO tracer for microglial activation. All patients underwent [11C]DPA713 PET scans twice, and the scans were conducted one year apart. The binding potential (BPND) of the tracer was estimated using a simplified reference tissue model. RESULTS [11C]DPA713 BPND measured at 6months after DMT was significantly higher in the MS group than that in the control group. Compared with the first PET measurement, the one-year PET measurement revealed significantly elevated [11C]DPA713 BPND in broader brain regions covering the temporal and parietal cortices after one year of DMT. CONCLUSIONS The current results indicate that microglial activation may proceed in the entire brain of clinically stable MS patients even after receiving DMT.