Miho Ota

Increased Binding of Peripheral Benzodiazepine Receptor in Alzheimer's Disease Measured by Positron Emission Tomography with [11C]DAA1106

BACKGROUND Peripheral benzodiazepine receptor (PBR) in the brain of Alzheimers disease (AD) patients has been discussed in relation to the role of gliosis in AD. The PBR was shown to have the ability to reflect activated glial cells, including microglia. The role of activated microglia in AD is an important topic in the pathophysiology of AD. The aim of this study was to quantify PBR in AD brain with a new high-sensitive PBR ligand, [(11)C]DAA1106. METHODS Positron emission tomography (PET) scans with [(11)C]DAA1106, a potent and selective ligand for PBR, were performed on 10 patients with AD and 10 age-matched control subjects. All patients had mild to moderate dementia. Duration of illness was 1-3 years at the time of the scans. The PBR binding in the regions of interest was quantified by binding potential (BP) obtained from compartmental model analysis with plasma input function. RESULTS Mean BP was increased in the brain of AD patients compared with control subjects in all measured regions. Statistical significance reached across many of the regions examined, including dorsal and medial prefrontal cortex, lateral temporal cortex, parietal cortex, occipital cortex, anterior cingulate cortex, striatum, and cerebellum. CONCLUSIONS The broad increase of PBR binding measured with [(11)C]DAA1106 in the brain of AD patients suggests a widespread existence of cellular reactions with PBR in relatively early-stage AD.

Age-related degeneration of corpus callosum measured with diffusion tensor imaging.

The corpus callosum is the major commissure connecting the cerebral hemispheres, and there is evidence of its change with aging. The sub-regions of the corpus callosum (genu, rostral body, anterior midbody, posterior midbody, isthmus, splenium) respectively comprise fibers connecting heteromodal- and unimodal-associated cortical regions, and it is known that abnormalities of the corpus callosum are correlated with abnormalities in cognition and behavior. Yet, little is known about changes in the tissue characteristics of its sub-regions. We assessed age-related changes in fractional anisotropy and mean diffusivity in the sub-regions of the corpus callosum using diffusion tensor imaging. We studied 42 healthy right-handed individuals aged 21-73 years. There were no significant interactions of sex x region. Age has significant negative correlation with fractional anisotropy in the genu (P < 0.001), rostral body (P < 0.001), and isthmus (P = 0.005). Fractional anisotropy of the anterior midbody was correlated negatively with age at a trend level (P = 0.022). Age was significantly positively correlated with mean diffusivity in the genu (P = 0.001), rostral body (P = 0.002), anterior midbody (P = 0.001), and isthmus (P = 0.001). Age-related changes were detected in the sub-regions where their projection areas are thought to be vulnerable to normal aging. This suggested that fractional anisotropy and mean diffusivity values of the corpus callosum sub-regions could serve as markers of disturbance across the respective projection areas.

Increased cerebrospinal fluid interleukin-6 levels in patients with schizophrenia and those with major depressive disorder

Elevated peripheral levels of interleukin-6 (IL-6) are common findings in schizophrenia and depression. However, previous studies that measured cerebrospinal fluid (CSF) IL-6 levels in these disorders reported controversial results. The present study examined whether CSF IL-6 levels are altered in patients with schizophrenia and those with depression. Lumbar punctures were performed in 32 patients with schizophrenia, 30 with major depressive disorder (MDD), and 35 healthy controls. Serum samples were simultaneously collected from all subjects in the patient groups and from 32 of the control group. CSF and serum IL-6 levels were determined by enzyme-linked immunosorbent assay. Both the patients with schizophrenia and MDD had significantly higher CSF IL-6 levels compared to the controls (schizophrenia: P = 0.0027; MDD: P = 0.012). IL-6 levels were significantly higher in the CSF than in the serum. No significant correlation was observed between CSF and serum IL-6 levels. The present findings suggest that IL-6 of central origin is associated with the pathophysiology of schizophrenia and MDD, although confounding effect of smoking status can not be entirely excluded.

Quantitative analysis for estimating binding potential of the peripheral benzodiazepine receptor with [11C]DAA1106

[11C]DAA1106 is a potent and selective ligand for the peripheral benzodiazepine receptor (PBR) with high affinity. It has been reported that the density of PBR is related to brain damage, so a reliable tracer method for the evaluation of PBR would be of use. We evaluated a quantification method of [11C]DAA1106 binding in simulated data and human brain data. In the simulation study, the reliability of parameters estimated from the nonlinear least-squares (NLS) method, graphical analysis (GA), and multilinear analysis (MA) was evaluated. In GA, variation of the estimated distribution volume (DV) was small. However, DV was underestimated as noise increased. In MA, bias was smaller, and variation of the estimated DV was larger than in GA. In NLS, although variation was larger than in GA, it was small enough in regions of interest analysis, and not only DV but also binding potential (BP), determined from the k3/k4 without any constraint, could be estimated. The variation of BP estimated with NLS became larger as k3 or k4 became smaller. In human studies with normal volunteers, regions of interest were drawn on several brain regions, BP was calculated by NLS, and DV was also estimated by NLS, GA, and MA. As a result, DVs estimated with each method were well correlated. However, there was no correlation between BP with NLS and DV with NLS, GA, and MA, because of the variation of K1/k2 between individuals. In conclusion, BP is estimated most reliably by NLS with the two-tissue compartment model.

Reduced serotonin transporter binding in the insular cortex in patients with obsessive-compulsive disorder: a [11C]DASB PET study.

The serotonin transporter (5-HTT) and other markers of the serotonergic system have been of interest in the pathophysiology of obsessive-compulsive disorder (OCD). Previous studies using single photon emission computed tomography (SPECT) with [(123)I]beta-CIT or positron emission tomography (PET) with [(11)C]McN5652 have not shown consistent findings about 5-HTT in OCD patients. The aim of the present study was to investigate 5-HTT binding using [(11)C]DASB, which has higher selectivity or specific binding-to-nonspecific binding ratios for 5-HTT compared to the aforementioned radioligands. Four drug-naive and 6 drug-free patients with OCD who were free of comorbid depression and 18 gender and age-matched healthy subjects underwent PET scans with [(11)C]DASB. The severity of OCD was assessed by Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) (mean+/-SD: 22+/-7.6, range: 7-32). The binding potential (BP(ND)) of [(11)C]DASB was calculated using a two-parameter multilinear reference tissue model (MRTM2). The parametric images of BP(ND) were analyzed using a statistical parametric mapping system. Significant reductions of BP(ND) were observed in the right posterior and left anterior insular cortices in patients with OCD compared to controls. Region-of-interest analysis has also confirmed significant reduction of BP(ND) in the insular cortex. Although significantly reduced BP(ND) in the orbitofrontal cortex was also observed in patients with OCD compared to controls, this finding should be considered with caution because of the very low 5-HTT binding in the region. On the other hand, no significant correlation was observed between the Y-BOCS score and BP(ND). The change in [(11)C]DASB binding in the insular cortex suggests that dysfunction of the serotonergic system in the limbic area might be involved in the pathophysiology of OCD.

Regional dopamine synthesis in patients with schizophrenia using L-[β-11C]DOPA PET

The dopamine hypothesis has been the most widely known theory concerning schizophrenia. However, the exact mechanism including presynaptic dopaminergic activity and its relationship with symptom severity still remains to be revealed. We measured presynaptic dopamine synthesis using positron emission tomography (PET) with L-[beta-(11)C]DOPA in 18 patients with schizophrenia (14 drug-naive and 4 drug-free patients) and 20 control participants. Dopamine synthesis rates, expressed as k(i) values, were obtained using a graphical method, and the occipital cortex was used as reference region. Regions of interest were placed on the prefrontal cortex, temporal cortex, anterior cingulate, parahippocampus, thalamus, caudate nucleus, and putamen. Psychopathology was assessed with the Positive and Negative Symptom Scale (PANSS). We found significantly higher k(i) values in patients than in controls in the left caudate nucleus, but not in the other regions. The k(i) values in the thalamus exhibited a significant positive correlation with the PANSS total scores. Furthermore, a significant positive correlation was observed between the PANSS positive subscale scores and k(i) values in the right temporal cortex. Patients with schizophrenia showed higher dopamine synthesis in the left caudate nucleus, and dopaminergic transmission in the thalamus and right temporal cortex might be implicated in the expression of symptoms in schizophrenia.

Negative correlation between cerebrospinal fluid oxytocin levels and negative symptoms of male patients with schizophrenia

BACKGROUND Accumulating evidence indicates that oxytocin plays an important role in social interactions. Previous studies also suggest altered oxytocin function in patients with schizophrenia and depression. However, few studies have examined the central oxytocin levels in these disorders. METHODS Cerebrospinal fluid (CSF) oxytocin levels were measured by ELISA in male participants consisting of 27 patients with schizophrenia, 17 with major depressive disorder (MDD), and 21 healthy controls. RESULTS CSF oxytocin levels of patients with schizophrenia or MDD did not differ significantly with healthy controls. The antidepressant dose or the Hamilton depression rating scale score did not significantly correlate with the oxytocin levels in MDD patients. CSF oxytocin levels in schizophrenic patients significantly negatively correlated with second generation antipsychotic dose (r=-0.49, P=0.010) but not with first generation antipsychotic dose (r=-0.13, P=0.50). A significant correlation was observed between oxytocin levels and negative subscale of PANSS (r=-0.38, P=0.050). This correlation remained significant even after controlling for second generation antipsychotic dose (r=-0.47, P=0.016). CONCLUSIONS We obtained no evidence of altered CSF oxytocin levels in patients with schizophrenia or those with MDD. However, lower oxytocin levels may be related to higher second generation antipsychotic dose and more severe negative symptoms in schizophrenia.

Possible association of Bifidobacterium and Lactobacillus in the gut microbiota of patients with major depressive disorder

BACKGROUND Bifidobacterium and Lactobacillus in the gut have been suggested to have a beneficial effect on stress response and depressive disorder. We examined whether these bacterial counts are reduced in patients with major depressive disorder (MDD) than in healthy controls. METHOD Bifidobacterium and Lactobacillus counts in fecal samples were estimated in 43 patients and 57 controls using bacterial rRNA-targeted reverse transcription-quantitative polymerase chain reaction RESULTS The patients had significantly lower Bifidobacterium counts (P=0.012) and tended to have lower Lactobacillus counts (P=0.067) than the controls. Individuals whose bacterial counts below the optimal cut-off point (9.53 and 6.49log10 cells/g for Bifidobacterium and Lactobacillus, respectively) were significantly more common in the patients than in the controls for both bacteria (Bifidobacterium: odds ratio 3.23, 95% confidence interval [CI] 1.38-7.54, P=0.010; Lactobacillus: 2.57, 95% CI 1.14-5.78, P=0.027). Using the same cut-off points, we observed an association between the bacterial counts and Irritable bowel syndrome. Frequency of fermented milk consumption was associated with higher Bifidobacterium counts in the patients. LIMITATIONS The findings should be interpreted with caution since effects of gender and diet were not fully taken into account in the analysis. CONCLUSION Our results provide direct evidence, for the first time, that individuals with lower Bifidobacterium and/or Lactobacillus counts are more common in patients with MDD compared to controls. Our findings provide new insight into the pathophysiology of MDD and will enhance future research on the use of pro- and prebiotics in the treatment of MDD.

Relationship between diffusion tensor imaging and brain morphology in patients with myotonic dystrophy

Myotonic dystrophy type 1 (MyD) is a common inherited neuromuscular disorder. In addition to neuromuscular symptoms, many MyD patients show central nervous system neuropathology. This study evaluated whether MyD patients display diffusion tensor (DT) abnormalities associated with regional cortical atrophy and clinical features. Three-dimensional T1-weighted and DT magnetic resonance images of the brain were obtained in 11 MyD patients and 13 age- and sex-matched healthy subjects. Fractional anisotropy (FA) and mean diffusivity (MD) values were calculated in corpus callosum subregions with DT imaging (DTI) along with volumetric changes, and correlations with clinical features were examined. Differences between MyD patients and healthy subjects were analyzed statistically. Significantly lower FA and higher MD values were found in the genu, rostral body, anterior midbody, posterior midbody and splenium in MyD patients than in control subjects (p<0.05, corrected; lower FA in the splenium was at a trend level). These corpus callosum subregions were the areas connected to cortical areas where significantly lower volumes were found in MyD patients. No significant decrease in volumes was noted in the parietal cortex, where connecting fibers pass through the isthmus in which DTI abnormalities were not detected in MyD patients. Significant negative correlations to volumes of frontal areas were noted, particularly bilateral motor areas, with cytosine thymine guanidine (CTG) triplet expansion. DTI results in corpus callosum may reflect morphological changes in the connecting cortical areas of MyD patients.

Degeneration of dementia with Lewy bodies measured by diffusion tensor imaging.

Dementia with Lewy bodies (DLB) is the second most common form of dementia. It is thought to involve impairment of the visual association area. In this study, we applied diffusion tensor imaging (DTI) to examine the microstructural interruption of visual association areas in patients with DLB. The DTI metrics of three visual association fibres – the inferior longitudinal fasciculus (ILF), visual pathway, and splenial fibres – were compared between 14 patients with DLB and 13 healthy subjects. The fractional anisotropy value of the ILF was significantly lower in patients with DLB than in healthy subjects. The difference in the mean diffusivity value of ILF was at trend level. The λ2,3 of ILF were significantly lower in patients with DLB; however, there was no difference in λ1. DTI metrics of the visual pathway and splenial fibres showed no differences between the groups. Our results showed degeneration of the ILF, which is responsible for visuospatial cognition. ILF dysfunction may influence the clinical features in DLB. Copyright