Yujiro Yoshihara

Hamamatsu University School of Medicine, Hamamatsu, Shizuoka-ken, Japan

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Publications (7)46.78 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: A growing body of evidence suggests that aberrant immunologic systems underlie the pathophysiologic characteristics of autism spectrum disorder (ASD). However, to our knowledge, no information is available on the patterns of distribution of microglial activation in the brain in ASD. To identify brain regions associated with excessively activated microglia in the whole brain, and to examine similarities in the pattern of distribution of activated microglia in subjects with ASD and control subjects. Case-control study using positron emission tomography and a radiotracer for microglia--[11C](R)-(1-[2-chrorophynyl]-N-methyl-N-[1-methylpropyl]-3 isoquinoline carboxamide) ([11C](R)-PK11195). Subjects recruited from the community. Twenty men with ASD (age range, 18-31 years; mean [SD] IQ, 95.9 [16.7]) and 20 age- and IQ-matched healthy men as controls. Diagnosis of ASD was made in accordance with the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised. Regional brain [11C](R)-PK11195 binding potential as a representative measure of microglial activation. The [11C](R)-PK11195 binding potential values were significantly higher in multiple brain regions in young adults with ASD compared with those of controls (P < .05, corrected). Brain regions with increased binding potentials included the cerebellum, midbrain, pons, fusiform gyri, and the anterior cingulate and orbitofrontal cortices. The most prominent increase was observed in the cerebellum. The pattern of distribution of [11C](R)-PK11195 binding potential values in these brain regions of ASD and control subjects was similar, whereas the magnitude of the [11C](R)-PK11195 binding potential in the ASD group was greater than that of controls in all regions. Our results indicate excessive microglial activation in multiple brain regions in young adult subjects with ASD. The similar distribution pattern of regional microglial activity in the ASD and control groups may indicate augmented but not altered microglial activation in the brain in the subjects with ASD.
    JAMA Psychiatry 01/2013; 70(1):49-58. · 12.01 Impact Factor
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    ABSTRACT: Brain β-amyloid (Aβ) deposition during normal aging is highlighted as an initial pathogenetic event in the development of Alzheimer's 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 [(18)F]FDG, Aβ deposits with [(11)C]PIB, and regional cerebral blood flow during control and working memory tasks by H(2)(15)O 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.
    Journal of Neuroscience 08/2011; 31(31):11193-9. · 6.91 Impact Factor
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    ABSTRACT: Both neuropsychological and functional magnetic resonance imaging studies have shown deficiencies in face perception in subjects with autism spectrum disorders (ASD). The fusiform gyrus has been regarded as the key structure in face perception. The cholinergic system is known to regulate the function of the visual pathway, including the fusiform gyrus. To determine whether central acetylcholinesterase activity, a marker for the cholinergic system, is altered in ASD and whether the alteration in acetylcholinesterase activity, if any, is correlated with their social functioning. Using positron emission tomography and a radiotracer, N-[(11)C]methyl-4-piperidyl acetate ([(11)C]MP4A), regional cerebrocortical acetylcholinesterase activities were estimated by reference tissue-based linear least-squares analysis and expressed in terms of the rate constant k(3). Current and childhood autism symptoms in the adult subjects with ASD were assessed by the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised, respectively. Voxel-based analyses as well as region of interest-based methods were used for between-subject analysis and within-subject correlation analysis with respect to clinical variables. Participants recruited from the community. Twenty adult subjects with ASD (14 male and 6 female; age range, 18-33 years; mean [SD] intelligence quotient, 91.6 [4.3]) and 20 age-, sex-, and intelligence quotient-matched healthy controls. Both voxel- and region of interest-based analyses revealed significantly lower [(11)C]MP4A k(3) values in the bilateral fusiform gyri of subjects with ASD than in those of controls (P < .05, corrected). The fusiform k(3) values in subjects with ASD were negatively correlated with their social disabilities as assessed by Autism Diagnostic Observation Schedule as well as Autism Diagnostic Interview-Revised. The results suggest that a deficit in cholinergic innervations of the fusiform gyrus, which can be observed in adults with ASD, may be related to not only current but also childhood impairment of social functioning.
    Archives of general psychiatry 03/2011; 68(3):306-13. · 12.26 Impact Factor
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    ABSTRACT: Amyloid 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. Eleven nootropic drug-naïve AD patients underwent a series of positron emission tomography (PET) measurements with [(11)C](R)PK11195, [(11)C]PIB and [(18)F]FDG and a battery of cognitive tests within the same day. The binding potentials (BPs) of [(11)C](R)PK11195 were directly compared with those of [(11)C]PIB in the brain regions with reduced glucose metabolism. BPs of [(11)C](R)PK11195 and [(11)C]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 [(11)C](R)PK11195 BPs, but not [(11)C]PIB, in the limbic, precuneus and prefrontal regions. Direct comparisons showed a significant negative correlation between [(11)C](R)PK11195 and [(11)C]PIB BPs in the posterior cingulate cortex (PCC) (p < 0.05, corrected) that manifested the most severe reduction in [(18)F]FDG uptake. A lack of coupling between microglial activation and amyloid deposits may indicate that Aβ accumulation shown by [(11)C]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.
    European Journal of Nuclear Medicine 02/2011; 38(2):343-51. · 4.53 Impact Factor
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    ABSTRACT: Accumulating evidence suggests that dysregulation of the immune system is involved in the pathophysiology of autism spectrum disorders (ASD). The aim of the study was to explore immunological markers in peripheral plasma samples from non-medicated subjects with high-functioning ASD. A multiplex assay for cytokines and chemokines was applied to plasma samples from male subjects with high-functioning ASD (n = 28) and matched controls (n = 28). Among a total of 48 analytes examined, the plasma concentrations of IL-1β, IL-1RA, IL-5, IL-8, IL-12(p70), IL-13, IL-17 and GRO-α were significantly higher in subjects with ASD compared with the corresponding values of matched controls after correction for multiple comparisons. The results suggest that abnormal immune responses as assessed by multiplex analysis of cytokines may serve as one of the biological trait markers for ASD.
    PLoS ONE 01/2011; 6(5):e20470. · 3.73 Impact Factor
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    ABSTRACT: 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, (11)C-2-B-carbomethoxy-3B-(4-fluorophenyl) tropane ((11)C-CFT), to elucidate the pathophysiologic characteristics of the dopamine system in early converters. 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 (11)C-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. 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 (11)C-CFT binding in the bilateral striatum (affected, -46%; unaffected, -35%). Regression analysis showed that the level of (11)C-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). The finding of bilateral reduction in the striatal (11)C-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.
    Journal of Nuclear Medicine 08/2010; 51(8):1250-7. · 5.77 Impact Factor
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    ABSTRACT: Investigation into the whole brain morphology of early onset schizophrenia (EOS) to date has been sparse. We studied the regional brain volumes in EOS patients, and the correlations between regional volume measures and symptom severity. A total of 18 EOS patients (onset under 16 years) and 18 controls matched for age, gender, parental socioeconomic status, and height were examined. Voxel-based morphometric analysis using the Brain Analysis Morphological Mapping (BAMM) software package was employed to explore alterations of the regional grey (GM) and white matter (WM) volumes in EOS patients. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). EOS patients had significantly reduced GM volume in the left parahippocampal, inferior frontal, and superior temporal gyri, compared with the controls. They also had less WM volume in the left posterior limb of the internal capsule and the left inferior longitudinal fasciculus. The positive symptom score of PANSS (higher values corresponding to more severe symptoms) was negatively related to GM volume in the bilateral posterior cingulate gyrus. The negative symptom score was positively correlated with GM volume in the right thalamus. As for the association with WM volume, the positive symptom score of PANSS was positively related to cerebellar WM (vermis region), and negatively correlated with WM in the brain stem (pons) and in the bilateral cerebellum (hemisphere region). Our findings of regional volume alterations of GM and WM in EOS patients coincide with those of previous studies of adult onset schizophrenia patients. However, in brain regions that had no overall structural differences between EOS patients and controls (that is, the bilateral posterior cingulate gyrus, the right thalamus, the cerebellum, and the pons), within-subject analysis of EOS patients alone revealed that there were significant associations of the volume in these areas and the symptom severity. These findings suggest that at an early stage of the illness, especially for those with onset before brain maturation, a wide range of disturbed neural circuits, including these brain regions that show no apparent morphological changes, may contribute to the formation of the symptomatology.
    Annals of General Psychiatry 01/2009; 7:25. · 1.57 Impact Factor

Publication Stats

108 Citations
46.78 Total Impact Points

Institutions

  • 2009–2013
    • Hamamatsu University School of Medicine
      • Research Center for Child Mental Development
      Hamamatsu, Shizuoka-ken, Japan
  • 2011
    • Kanazawa University
      • Research Center for Child Mental Development
      Kanazawa, Ishikawa, Japan