Tomohisa Nagashima

Abnormalities of the uncinate fasciculus and posterior cingulate fasciculus in mild cognitive impairment and early Alzheimer's disease: a diffusion tensor tractography study.

Mild cognitive impairment (MCI) is considered the transitional stage between normal cognition and dementia. The aim of this study was to use tractography based analysis to elucidate alterations in subjects with MCI compared with subjects with early Alzheimers disease (AD) and controls. Seventeen subjects with early AD, 16 with MCI and 16 controls underwent magnetic resonance diffusion tensor imaging (DTI) and neuropsychological assessment. Diffusion tensor tractographies were computed and fiber-tract maps were generated using dTV II DTI software. We measured mean fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values along the uncinate fasciculus (UNC), posterior cingulate fasciculus (PCF) and corticospinal tract (CST). There were statistically significant differences in the FA and ADC values of the UNC and PCF between subjects with early AD and controls. Subjects with MCI exhibited significantly lower FA values on both sides of the PCF relative to controls. However, there were no significant differences between subjects with early AD and MCI for any measurement. Our results suggest that alterations in the PCF precede the onset of dementia.

White matter changes in dementia with Lewy bodies and Alzheimer’s disease: A tractography-based study

Dementia with Lewy bodies (DLB) and Alzheimers disease (AD) are different types of dementia. However, their clinical symptoms partially overlap and differential diagnosis is occasionally difficult. There is need for additional diagnostic criteria to reliably differentiate between these two conditions. Meanwhile, several imaging studies have showed inconsistent results between DLB and AD. The aim of this study was to use a tractography-based analysis to elucidate white matter alterations in subjects with DLB compared to those with AD and to controls. An understanding of the white matter connectivity differences between AD, DLB and controls will be helpful for differential diagnosis and an understanding of the pathophysiology. Twenty-six subjects with DLB, 26 with AD and 26 controls underwent magnetic resonance diffusion tensor imaging and neuropsychological assessment. Diffusion tensors were computed and fiber-tract maps were created using dTV II software. We measured mean fractional anisotropy (FA) values along the uncinate fasciculus (UNC), the inferior occipitofrontal fasciculus (IOFF) and the inferior longitudinal fasciculus (ILF). Both subjects with DLB and AD had lower FA values for the bilateral UNC than controls. Subjects with DLB exhibited significantly lower FA values on both sides of the IOFF and the left side of the ILF than those of controls. Although there were no significant differences between subjects with DLB and AD for any measurements, those with DLB exhibited lower FA values especially in visual-related white matter. These different changes in white matter tracts among groups could be helpful for differential diagnosis and an understanding of the pathophysiology.

Brain structural changes and neuropsychological impairments in male polydipsic schizophrenia

BackgroundPolydipsia frequently occurs in schizophrenia patients. The excessive water loading in polydipsia occasionally induces a hyponatremic state and leads to water intoxication. Whether polydipsia in schizophrenic patients correlates with neuropsychological impairments or structural brain changes is not clear and remains controversial.MethodsEight polydipsic schizophrenia patients, eight nonpolydipsic schizophrenia patients, and eight healthy controls were recruited. All subjects underwent magnetic resonance imaging (MRI) and neuropsychological testing. Structural abnormalities were analyzed using a voxel-based morphometry (VBM) approach, and patients’ neuropsychological function was assessed using the Brief Assessment of Cognition in Schizophrenia, Japanese version (BACS-J).ResultsNo significant differences were found between the two patient groups with respect to the clinical characteristics. Compared with healthy controls, polydipsic patients showed widespread brain volume reduction and neuropsychological impairment. Furthermore, the left insula was significantly reduced in polydipsic patients compared with nonpolydipsic patients. These nonpolydipsic patients performed intermediate to the other two groups in the neuropsychological function test.ConclusionsIt is possible that polydipsia or the secondary hyponatremia might induce left insula volume reduction. Furthermore, this structural brain change may indirectly induce more severe neuropsychological impairments in polydipsic patients. Thus, we suggest that insula abnormalities might contribute to the pathophysiology of polydipsic patients.

PET quantification of the norepinephrine transporter in human brain with (S,S)-18F-FMeNER-D2

Norepinephrine transporter (NET) in the brain plays important roles in human cognition and the pathophysiology of psychiatric disorders. Two radioligands, (S,S)-11C-MRB and (S,S)-18F-FMeNER-D2, have been used for imaging NETs in the thalamus and midbrain (including locus coeruleus) using PET in humans. However, NET density in the equally important cerebral cortex has not been well quantified because of unfavorable kinetics with (S,S)-11C-MRB and defluorination with (S,S)-18F-FMeNER-D2, which can complicate NET quantification in the cerebral cortex adjacent to the skull containing defluorinated 18F radioactivity. In this study, we have established analysis methods of quantification of NET density in the brain including the cerebral cortex using (S,S)-18F-FMeNER-D2 PET. Methods: We analyzed our previous (S,S)-18F-FMeNER-D2 PET data of 10 healthy volunteers dynamically acquired for 240 min with arterial blood sampling. The effects of defluorination on the NET quantification in the superficial cerebral cortex was evaluated by establishing a time stability of NET density estimations with an arterial input 2-tissue-compartment model, which guided the less-invasive reference tissue model and area under the time–activity curve methods to accurately quantify NET density in all brain regions including the cerebral cortex. Results: Defluorination of (S,S)-18F-FMeNER-D2 became prominent toward the latter half of the 240-min scan. Total distribution volumes in the superficial cerebral cortex increased with the scan duration beyond 120 min. We verified that 90-min dynamic scans provided a sufficient amount of data for quantification of NET density unaffected by defluorination. Reference tissue model binding potential values from the 90-min scan data and area under the time–activity curve ratios of 70- to 90-min data allowed for the accurate quantification of NET density in the cerebral cortex. Conclusion: We have established methods of quantification of NET densities in the brain including the cerebral cortex unaffected by defluorination using (S,S)-18F-FMeNER-D2. These results suggest that we can accurately quantify NET density with a 90-min (S,S)-18F-FMeNER-D2 scan in broad brain areas.

Occupancy of Norepinephrine Transporter by Duloxetine in Human Brains Measured by Positron Emission Tomography with (S,S)-[18F]FMeNER-D2

Abstract Background The norepinephrine transporter in the brain has been targeted in the treatment of psychiatric disorders. Duloxetine is a serotonin and norepinephrine reuptake inhibitor that has been widely used for the treatment of depression. However, the relationship between dose and plasma concentration of duloxetine and norepinephrine transporter occupancy in the human brain has not been determined. In this study, we examined norepinephrine transporter occupancy by different doses of duloxetine. Methods We calculated norepinephrine transporter occupancies from 2 positron emission tomography scans using (S,S)-[18F]FMeNER-D2 before and after a single oral dose of duloxetine (20 mg, n = 3; 40 mg, n = 3; 60 mg, n =2). Positron emission tomography scans were performed from 120 to 180 minutes after an i.v. bolus injection of (S,S)-[18F]FMeNER-D2. Venous blood samples were taken to measure the plasma concentration of duloxetine just before and after the second positron emission tomography scan. Results Norepinephrine transporter occupancy by duloxetine was 29.7% at 20 mg, 30.5% at 40 mg, and 40.0% at 60 mg. The estimated dose of duloxetine inducing 50% norepinephrine transporter occupancy was 76.8 mg, and the estimated plasma drug concentration inducing 50% norepinephrine transporter occupancy was 58.0 ng/mL. Conclusions Norepinephrine transporter occupancy by clinical doses of duloxetine was approximately 30% to 40% in human brain as estimated using positron emission tomography with (S,S)-[18F]FMeNER-D2.

White matter changes in dementia with Lewy bodies and Alzheimer's disease: A tractgraphy-based study

s / Neuroscience Research 71S (2011) e108–e415 e289 P3-q14 Investigating the pathology of Alzheimer’s disease related to calcineurin in astrocytes Kiwamu Watanabe 1 , Masato Maesako 2, Megumi Asada 2, Akira Kuzuya 1, Kengo Uemura 1, Haruhiko Akiyama 3, Ryosuke Takahashi 1, Ayae Kinoshita 2 1 Dept. of Neurol., Grad. Sch. of Med., Kyoto Univ., Kyoto, Japan 2 Sch. of Human Health Science., Grad. Sch. of Med., Kyoto Univ., Kyoto, Japan 3 Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan Activation of glial cells is one of the well-known pathological features of Alzheimer’s disease (AD). Previous reports indicate that the calcium/calmodulin-dependent protein phosphatase, calcineurin (CaN), plays an important role in neuroinflammation. Others denoted that tumor necrosis factor-alpha (TNF) contributes to neuronal apoptosis. Based on previous literature, we hypothesized as follows; in astrocytes, intracellular calcium influx, evoked by extracellular amyloid beta (A ), leads to an activation of CaN. CaN, in turn, leads to the nuclear translocation of the nuclear factor of activated T cell (NFAT) to function as a transcriptional factor. As a result, TNFis released from astrocytes, leading to neuronal damage. In order to clarify this hypothesis, we checked the activation of CaN by A 42 peptide by western blotting (WB) and the translocation of NFAT by the immunostaining in primary astrocytes. At the same time, we measured the amount of TNFin that culture medium by an enzyme-linked immunosorbent assay (ELISA). We evaluated the damage of primary neurons by co-culturing with primary astrocytes, which express constitutively-active calcineurin construct. We acquired a supportive data for our hypothesis, suggesting that glial cells are closely involved in AD and can be a new therapeutic target. doi:10.1016/j.neures.2011.07.1260 P3-q15 Amyloid peptides reduce theta oscillations in the hippocampus Shota Sato 1 , Nagisa Yoshida 1, Takashi Katsu 1, Toshiharu Suzuki 2, Tsuyoshi Inoue 1 1 Dept of Biophys Chem, Grad Sch of Med Dent and Pharm Sci, Okayama Univ, Okayama 2 Dept of Neurosci, Grad Sch of Pharm Sci, Hokkaido Univ, Sapporo Amyloid (A ) protein is a very important factor of Alzheimer’s disease, and it is considered that A causes neurodegeneration in the hippocampus and leads to Alzheimer’s disease. Recent works showed that A inhibits synaptic plasticity at cellular levels, and impairs memory acquisition at behavioral levels. However, it is unknown how A works at the level of neural circuit. To address this issue, we examined the theta oscillation (EEG of 4–7 Hz, related to learning and memory) that derived from the neural circuit activity in the hippocampus. We recorded the theta oscillation in the hippocampal CA3 region of awake mice, and then applied A oligomer form or fibril form to the cerebral ventricle. Administration of saline as a control induced little changes in the power of theta oscillation, but A oligomer remarkably decreased the power of theta oscillation. These results show that A acts on the hippocampal neural circuit and attenuate the theta oscillation. Furthermore, there were a little changes of the theta oscillation when A fibril was administered. This suggests that the neurotoxicity of A is strongly dependent on the degree of aggregation. doi:10.1016/j.neures.2011.07.1261 P3-q16 Selective autophagy in neurons and its involvement in the tau pathogenesis Maiko Ono , Bin Ji, Masahiro Maruyama, Jun Maeda, Takeharu Minamihisamatsu, Tetsuya Suhara, Makoto Higuchi Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan In Alzheimer’s disease, hyperphosphorylated tau proteins assemble into fibrils, making up neurofibrillary tangles (NFTs), and are involved in neuronal loss. It is hypothesized that packaging of abnormal tau into NFTs protects neurons against tau-induced neurodegeneration, while molecular mediators of NFT formation versus accumulation of neurotoxic, low-order tau assemblies remain unidentified. p62 promotes autophagic degradation of ubiquitinated proteins, and sequesters them by forming an inclusion body. In mice transgenic for mutant human P301S tau protein, NFTs are abundantly developed in the spinal cord and brainstem but are accompanied by only modest neuronal loss in these areas. By contrast, massive neuron death without deposition of NFTs occurs in the hippocampus. Here, we investigated regional differences in levels of p62 and their association with tau lesions between the brainstem and hippocampus of P301S and wild-type mice to analyze roles of p62 in the tau pathogenesis. Immunoreactivity for p62 was found in brainstem neurons of wild-type mice, and this immunolabeling was markedly intensified with accumulation of phosphorylated and ubiquitinated tau in P301S mice, indicating recruitment of p62 to packaging of hyperphosphorylated and ubiquitinated tau. Meanwhile, p62 was barely detectable in somas of hippocampal pyramidal neurons in both wild-type and P301S mice. In these hippocampal neurons, diffuse signals of phosphorylated tau spatially overlapped with ubiquitin but not p62 immunoreactivity. Moreover, autophagic activities in the hippocampus were higher than that in the brainstem as assessed by immunoblotting for LC3. These findings suggest that p62 and other components of autophagy are constitutively consumed at high levels in hippocampal neurons of P301S mice, leading to insufficient reserve capacity for autophagic clearance of hyperphosphorylated tau and its segregation into inclusions and eventually neurotoxicity by misfolded but unpackaged tau. doi:10.1016/j.neures.2011.07.1262 P3-q17 White matter changes in dementia with Lewy bodies and Alzheimer’s disease: A tractgraphy-based study Soichiro Kitamura 1 , Kuniaki Kiuchi 1, Masayuki Morikawa 2, Toshiaki Taoka 3, Tomohisa Nagashima 1, Kazuhiko Yamamuro 1, Hiroki Yoshino 1, Tomohiko Takeda 1, Miyuki Sadamatsu 1, Kimihiko Kichikawa 3, Toshifumi Kishimoto 1 1 Departmet of Psychiatry, Nara Medical Univ, Nara, Japan 2 Sakai City Medical Center, Sakai, Japan 3 Department of Radiology, Nara Medical University, Nara, Japan Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) are common cause of cognitive decline, and are different types of dementia. However, these clinical features overlap partially and it is sometimes difficult to diagnose these diseases. It is needed for additional diagnostic criteria to precisely differentiate between these two diseases. Meanwhile, several imaging studies have showed inconsistent results between DLB and AD. The aim of this study was to elucidate white matter alterations in subjects with DLB compared to those with AD and to controls with tractography-based analysis. 26 subjects with DLB, 26 with AD and 26 controls underwent magnetic resonance diffusion tensor imaging and neuropsychological assessment. Diffusion tensors were computed and fiber-tract maps were created using Volume-one and dTV II software. We measured and investigated mean fractional anisotropy (FA) values along the uncinate fasciculus (UNC), the inferior occipitofrontal fasciculus (IOFF) and the inferior longitudinal fasciculus (ILF). Both subjects with DLB and AD had lower FA values for the bilateral UNC than controls. Subjects with DLB exhibited significantly lower FA values on both sides of the IOFF and the left side of the ILF than those of controls. Although there were no significant differences between subjects with DLB and AD for any measurements, those with DLB exhibited lower FA values especially in the visual-related white matter bundles. These differential white matter changes among groups might be helpful for understanding of the pathophysiology and differential diagnosis of these diseases. doi:10.1016/j.neures.2011.07.1263 P3-q18 Functional complementation of hippocampus with exogenous neural stem cells for cognitive recovery after application of kainic acid Mitsunori Arai , Takumi Yamamoto, Shoji Komai

Reduced white matter integrity in attention-deficit hyperactivity disorder: Whole-brain voxel-wise investigation

SOX10 is a transcription factor that is essential for the neural crest development and the myelin formation both in the PNS and CNS. SOX10 mutations are associated with two distinct neurocristopathies, Waardenburg-Hirschsprung disease (WS4) and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung disease (PCWH), latter of which shows more complex and severe neurological phenotype. Clinical and molecular findings suggested that WS4 results form haploinsufficiency of SOX10, while PCWH is predicted to results from SOX10 acting as either dominant-negative or gain-of-function allele. Although model animals are available for WS4, no animal models for PCWH are currently present. To determine the molecular mechanisms for PCWH in vivo, we have founded BAC-transgenic mice (Tg) carrying a PCWH-causing mutant Sox10 construct. Tg showed abnormal motor coordination, circling behavior, hypopigmented coat color, perceptive deafness, and abnormal enlargement of colon. Microscopic examinations in nerve systems showed relatively normal migration and differentiation of oligodendrocyte and Schwann cells, but apparently delayed myelination in Tg mice. These findings suggested that the mutant Sox10 Tg mice mimic phenotypes observed in human patients with PCWH and thus serve as a model for PCWH.

Type D Syndrome of Inappropriate Antidiuretic Hormone Secretion in a Schizophrenia Patient with Polydipsia

A 55-year-old man with schizophrenia developed water intoxication due to primary polydipsia. His manner of antidiuretic hormone secretion was investigated by water loading and infusion of hypertonic saline to clarify the form of the syndrome of inappropriate antidiuretic hormone secretion. The plasma antidiuretic hormone level, which may be involved in the occurrence of water intoxication, was consistently low in this patient, and linked to type D syndrome of inappropriate antidiuretic hormone secretion, designated “hypovasopressinemic antidiuresis”. Although this type is not common, it should be considered as a pathophysiology for water intoxication in schizophrenia patients.