PET-detectable tau pathology correlates with long-term neuropsychiatric outcomes in patients with traumatic brain injury.

Tau deposits is a core feature of neurodegenerative disorder following traumatic brain injury (TBI). Despite ample evidence from post-mortem studies demonstrating exposure to both mild-repetitive and severe TBIs are linked to tau depositions, associations of topology of tau lesions with late-onset psychiatric symptoms due to TBI have not been explored. To address this issue, we assessed tau deposits in long-term survivors of TBI by PET with 11C-PBB3, and evaluated those associations with late-life neuropsychiatric outcomes. PET data were acquired from 27 subjects in the chronic stage following mild-repetitive or severe TBI and 15 healthy control subjects. Among the TBI patients, 14 were diagnosed as having late-onset symptoms based on the criteria of traumatic encephalopathy syndrome. For quantification of tau burden in TBI brains, we calculated 11C-PBB3 binding capacity (cm3), which is a summed voxel value of binding potentials (BP*ND) multiplied by voxel volume. Main outcomes of the present study were differences in 11C-PBB3 binding capacity between groups, and the association of regional 11C-PBB3 binding capacity with neuropsychiatric symptoms. To confirm 11C-PBB3 binding to tau deposits in TBI brains, we conducted in vitro PBB3 fluorescence and phospho-tau antibody immunofluorescence labelling of brain sections of chronic traumatic encephalopathy obtained from the Brain Bank. Our results showed that patients with TBI had higher 11C-PBB3 binding capacities in the neocortical grey and white matter segments than healthy control subjects. Furthermore, TBI patients with traumatic encephalopathy syndrome showed higher 11C-PBB3 binding capacity in the white matter segment than those without traumatic encephalopathy syndrome, and regional assessments revealed that subgroup difference was also significant in the frontal white matter. 11C-PBB3 binding capacity in the white matter segment correlated with the severity of psychosis. In vitro assays demonstrated PBB3-positive tau inclusions at the depth of neocortical sulci, confirming 11C-PBB3 binding to tau lesions. In conclusion, increased 11C-PBB3 binding capacity is associated with late-onset neuropsychiatric symptoms following TBI, and a close correlation was found between psychosis and 11C-PBB3 binding capacity in the white matter.

Updating the neuropsychological test system in Japan for the elderly and in a modern touch screen tablet society by resetting the cut-off values.

AIM: Covert hepatic encephalopathy is frequently seen in cirrhotic patients. This condition can be diagnosed by a computerized neuropsychological test system (NPT); however, NPT has not been updated for approximately two decades in Japan. The aim of this study is to update the NPT to be more suitable for both the elderly and modern society by resetting of cut-off values. METHODS: We enrolled 367 healthy subjects aged between 40 and 79 years old between 2003 and 2010. The NPT consists of the following eight tests: number connection tests (NCT)-A and -B, a figure position test, a digit symbol test, a block design test, and reaction time tests (RTT)-A, -B, and -C. All subjects were classified into eight groups (5-year quartile ranges from 40 to 79 years old), and the cut-off value for each test was compared to the former cut-off value (NPT version 1). RESULTS: In all eight tests, most of the cut-off values were different from those in NPT version 1. The difference was minimal in RTT-A, RTT-B, and RTT-C. However, the difference was evident in the NCT-A, NCT-B, digit symbol test, and block design test. In particular, a 57.8-s decrease in the cut-off value was seen in the 65-69-year-old group for the NCT-B test (71.3 s vs. 129.1 s). CONCLUSIONS: We updated the NPT by covering subjects aged 40-79 years and resetting the cut-off values. Thus, the updated NPT is an elderly and modern subject-compliant application. This update may improve the diagnostic ability of covert hepatic encephalopathy in contemporary cirrhotic patients.

Disappearance of treatment-resistant depression after damage to the orbitofrontal cortex and subgenual cingulate area: a case study.

BACKGROUND: Although post-stroke depression is a well-characterized disorder, there is less understanding of how pre-existence of depression is affected by a stroke. CASE PRESENTATION: We describe a patient with treatment-resistant major depression, which had been ongoing for 14 years but disappeared shortly after onset of a subarachnoid hemorrhage. Her cognitive function and functional status were mostly unaffected by the stroke. However, she no longer excessively regretted past events. Lesions were found in the orbitofrontal cortex, which is involved in feeling regret, and in the adjacent subgenual cingulate area, which is metabolically hyperactive in treatment-resistant depression and is the target for deep-brain stimulation for relief of treatment-resistant depression. The lesions from the stroke may have caused the disappearance of the patient's treatment-resistant depression by alleviating excessive regret and decreasing the elevated activity in these areas. CONCLUSIONS: This patient's clinical course may shed light on the neuropsychological and neurophysiological mechanisms of major depression of the melancholic subtype.

The Japanese version of the Rapid Dementia Screening Test is effective compared to the clock-drawing test for detecting patients with mild Alzheimer's disease.

BACKGROUND: The Japanese version of the Rapid Dementia Screening Test (RDST-J) and the clock-drawing test (CDT) are both brief psychometric screening tools used to detect the severity of Alzheimer's disease. It remains unclear, however, which is more effective when screening for mild Alzheimer's disease. METHODS: We administered the RDST-J and CDT to 250 patients with very mild to severe Alzheimer's disease and to 49 healthy volunteers. Patients with a Mini-Mental State Examination score of 12-26 had Clinical Dementia Rating (CDR) scores from 0.5 to 3. Patients were divided into four groups according to CDR score. We performed one-way factorial anova between the four groups and control subjects based on the CDT and RDST-J scores. RESULTS: Data analysis revealed that RDST-J could distinguish patients with CDR 0.5 from the controls, but CDT could not. Furthermore, the sensitivity of a RDST-J score ≥8 was 57.1%, with a specificity of 81.0%, and the sensitivity of a RDST-J score ≥9 was 79.6%, with a specificity of 55.1% for discriminating CDR 0.5 from controls. CONCLUSIONS: RDST-J is a more effective tool than CDT for distinguishing CDR 0.5 from controls.

Honesty mediates the relationship between serotonin and reaction to unfairness.

How does one deal with unfair behaviors? This subject has long been investigated by various disciplines including philosophy, psychology, economics, and biology. However, our reactions to unfairness differ from one individual to another. Experimental economics studies using the ultimatum game (UG), in which players must decide whether to accept or reject fair or unfair offers, have also shown that there are substantial individual differences in reaction to unfairness. However, little is known about psychological as well as neurobiological mechanisms of this observation. We combined a molecular imaging technique, an economics game, and a personality inventory to elucidate the neurobiological mechanism of heterogeneous reactions to unfairness. Contrary to the common belief that aggressive personalities (impulsivity or hostility) are related to the high rejection rate of unfair offers in UG, we found that individuals with apparently peaceful personalities (straightforwardness and trust) rejected more often and were engaged in personally costly forms of retaliation. Furthermore, individuals with a low level of serotonin transporters in the dorsal raphe nucleus (DRN) are honest and trustful, and thus cannot tolerate unfairness, being candid in expressing their frustrations. In other words, higher central serotonin transmission might allow us to behave adroitly and opportunistically, being good at playing games while pursuing self-interest. We provide unique neurobiological evidence to account for individual differences of reaction to unfairness.

Norepinephrine transporter occupancy by nortriptyline in patients with depression: a positron emission tomography study with (S,S)-[¹8F]FMeNER-D2.

Norepinephrine transporter (NET) plays important roles in the treatment of various neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder (ADHD). Nortriptyline is a NET-selective tricyclic antidepressant (TCAs) that has been widely used for the treatment of depression. Previous positron emission tomography (PET) studies have reported over 80% serotonin transporter occupancy with clinical doses of selective serotonin reuptake inhibitors (SSRIs), but there has been no report of NET occupancy in patients treated with relatively NET-selective antidepressants. In the present study, we used PET and (S,S)-[18¹8F]FMeNER-D2 to investigate NET occupancies in the thalamus in 10 patients with major depressive disorder taking various doses of nortriptyline, who were considered to be responders to the treatment. Reference data for the calculation of occupancy were derived from age-matched healthy controls. The result showed approximately 50-70% NET occupancies in the brain as a result of the administration of 75-200 mg/d of nortriptyline. The estimated effective dose (ED50) and concentration (EC50) required to induce 50% occupancy was 65.9 mg/d and 79.8 ng/ml, respectively. Furthermore, as the minimum therapeutic level of plasma nortriptyline for the treatment of depression has been reported to be 70 ng/ml, our data indicate that this plasma nortriptyline concentration corresponds to approximately 50% NET occupancy measured with PET, suggesting that more than 50% of central NET occupancy would be appropriate for the nortriptyline treatment of patients with depression.

Progression of logopenic variant primary progressive aphasia to apraxia and semantic memory deficits.

BACKGROUND: Due to the nature of neurodegenerative disorders, patients with primary progressive aphasia develop cognitive impairment other than aphasia as the disorder progresses. The progression of logopenic variant primary progressive aphasia (lvPPA), however, has not been well described. In particular, praxic disorders and semantic memory deficits have rarely been reported. CASE PRESENTATIONS: We report three patients in the initial stage of lvPPA who subsequently developed apraxia in the middle stage and developed clinically evident semantic memory deficits in the advanced stages. CONCLUSIONS: The present case series suggests that some patients with lvPPA develop an atypical type of dementia with apraxia and semantic memory deficits, suggesting that these cases should be classified as a type of early-onset Alzheimer's disease.

Increased left anterior insular and inferior prefrontal activity in post-stroke mania.

BACKGROUND: Post-stroke mania is an infrequent complication after stroke, and the mechanisms underlying this disorder remain unclear. Although a contralesional release phenomenon has been implicated in post-stroke mania, empirical findings are lacking. CASE PRESENTATION: We present a case report of post stroke mania. Single photon emission tomography (SPECT) was performed twice, during the manic state and during the remitted euthymic state. The first SPECT study performed during the manic state demonstrated hypoperfusion in the right temporal and frontal regions due to right putaminal hemorrhage. It also showed hyperperfusion in the inferior lateral prefrontal lobe, the temporal lobe, and the medial and lateral parts of the parietal lobe in the left hemisphere. The second SPECT study performed during the euthymic state demonstrated moderate improvement in the hypoperfusion in the right fronto-temporal regions. Furthermore, compared to the findings on the first SPECT study, the second study showed that the focal hyperperfusion in the anterior insular cortex, inferior lateral prefrontal lobes, and superior-middle temporal gyrus in the left hemisphere had vanished. CONCLUSION: Increased left inferior prefrontal and anterior insular activity and reduced extensive right fronto-temporal lobe activity are involved in the development of post-stroke mania.

Successful treatment of dopamine dysregulation syndrome with dopamine D2 partial agonist antipsychotic drug.

Dopamine dysregulation syndrome (DDS) consists of a series of complications such as compulsive use of dopaminergic medications, aggressive or hypomanic behaviors during excessive use, and withdrawal states characterized by dysphoria and anxiety, caused by long-term dopaminergic treatment in patients with Parkinson's disease (PD). Although several ways to manage DDS have been suggested, there has been no established treatment that can manage DDS without deterioration of motor symptoms. In this article, we present a case of PD in whom the administration of the dopamine D2 partial agonistic antipsychotic drug aripiprazole improved DDS symptoms such as craving and compulsive behavior without worsening of motor symptoms. Considering the profile of this drug as a partial agonist at D2 receptors, it is possible that it exerts its therapeutic effect on DDS by modulating the dysfunctional dopamine system.

Poor performance on the Iowa gambling task in children with obsessive-compulsive disorder.

BACKGROUND: Several lines of evidence implicate orbitofrontal cortex dysfunction in the pathophysiology of obsessive-compulsive disorder (OCD). The purpose of this study was to investigate neuropsychological dysfunction of the orbitofrontal cortex in children with OCD. METHODS: The Iowa Gambling Task (IGT), which reflects orbitofrontal cortex function, and the Wisconsin Card Sorting Test (WCST), which is associated with functioning of the dorsolateral prefrontal cortex, were administered to 22 children with OCD and 22 healthy controls matched for gender, age, and intelligence. RESULTS: OCD patients displayed poor performance on the IGT. In contrast, performance on the WCST was not impaired in OCD patients compared to controls. CONCLUSIONS: These findings are in line with previous studies demonstrating that OCD in childhood is associated with a dysfunction of orbitofrontal-striatal-thalamic circuitry.

Contribution of dopamine D1 and D2 receptors to amygdala activity in human.

Several animal studies have demonstrated functional roles of dopamine (DA) D1 and D2 receptors in amygdala activity. However, the contribution of DA D1 and D2 receptors to amygdala response induced by affective stimuli in human is unknown. To investigate the contribution of DA receptor subtypes to amygdala reactivity in human, we conducted a multimodal in vivo neuroimaging study in which DA D1 and D2 receptor bindings in the amygdala were measured with positron emission tomography (PET), and amygdala response induced by fearful faces was assessed by functional magnetic resonance imaging (fMRI) in healthy volunteers. We used multimodality voxelwise correlation analysis between fMRI signal and DA receptor binding measured by PET. DA D1 binding in the amygdala was positively correlated with amygdala signal change in response to fearful faces, but DA D2 binding in the amygdala was not related to amygdala signal change. DA D1 receptors might play a major role in enhancing amygdala response when sensory inputs are affective.

Dopamine D1 receptors and nonlinear probability weighting in risky choice.

Misestimating risk could lead to disadvantaged choices such as initiation of drug use (or gambling) and transition to regular drug use (or gambling). Although the normative theory in decision-making under risks assumes that people typically take the probability-weighted expectation over possible utilities, experimental studies of choices among risks suggest that outcome probabilities are transformed nonlinearly into subjective decision weights by a nonlinear weighting function that overweights low probabilities and underweights high probabilities. Recent studies have revealed the neurocognitive mechanism of decision-making under risk. However, the role of modulatory neurotransmission in this process remains unclear. Using positron emission tomography, we directly investigated whether dopamine D1 and D2 receptors in the brain are associated with transformation of probabilities into decision weights in healthy volunteers. The binding of striatal D1 receptors is negatively correlated with the degree of nonlinearity of weighting function. Individuals with lower striatal D1 receptor density showed more pronounced overestimation of low probabilities and underestimation of high probabilities. This finding should contribute to a better understanding of the molecular mechanism of risky choice, and extreme or impaired decision-making observed in drug and gambling addiction.

Serotonergic neurotransmission in the living human brain: a positron emission tomography study using [¹¹C]dasb and [¹¹C]WAY100635 in young healthy men.

The central serotonergic (5-HT) system is closely involved in regulating various mental functions such as mood and emotion. In this system, the serotonin transporter (5-HTT) and the 5-HT(1A) receptor play important roles in the pathophysiology and treatment of mood and anxiety disorders. However, only a few integrated databases have considered the intraindividual relationship between pre- and postsynaptic serotonergic transmission. In the present study, we constructed a database of 5-HTT and 5-HT(1A) receptors using positron emission tomography (PET) with [¹¹C]DASB and [¹¹C]WAY100635, respectively. Seventeen healthy young men participated in this study. After anatomic standardization of original images, BP(ND) was calculated on a voxel-by-voxel basis using reference tissue methods. The highest binding to 5-HTT was observed in the dorsal raphe nucleus, striatum, and thalamus; moderate binding, in the insula and cingulate cortex; and very low binding, in the cerebral neocortex. In contrast, the highest binding to 5-HT(1A) receptors was seen in the hippocampal regions, insula, neocortical regions, and dorsal raphe nucleus, and very low binding was found in the thalamus and basal ganglia. These distribution patterns were in agreement with those reported in human postmortem studies and previous PET investigations. In addition, exploratory analysis indicated significant negative correlations between the BP(ND) values with both radiotracers in certain regions of the brain, such as the cingulate, insula, and frontal, temporal and parietal cortices (Pearson's correlation, P < 0.05). These databases facilitate the understanding of the regional distribution of serotonergic neurotransmission function in the living human brain and the pathophysiology of various neuropsychiatric disorders.

Remission in schizophrenia: a community-based 6-year follow-up study in Bali.

AIM: The purpose of this naturalistic study was to investigate the rate and predictors of remission at medium-term follow up of individuals with schizophrenia in a community setting in Bali. METHODS: Subjects comprised 37 individuals with schizophrenia, including 19 never-treated cases, screened from 8546 general residents. Outcome was evaluated using the standardized symptomatic remission criteria based on Positive and Negative Syndrome Scale scores and operational functional remission criteria at 6-year follow up. RESULTS: Ten individuals (27%) achieved symptomatic remission, 12 (32%) achieved functional remission, and 10 (27%) achieved complete remission (i.e. symptomatic and functional remission). Lower Positive and Negative Syndrome Scale negative symptom score at baseline and receipt of psychiatric treatment for more than half of the follow-up period were predictors of complete remission. CONCLUSIONS: The majority of community-screened individuals with schizophrenia failed to achieve complete remission at the 6-year follow up. These results suggest that strategies promoting mental health service utilization among individuals with schizophrenia are essential in Bali.

Unmet supportive needs of cancer patients in an acute care hospital in Japan--a census study.

PURPOSE: Little research has been done on supportive needs of cancer patients in acute hospitals in Japan. This study aims to comprehensively assess the unmet supportive needs of hospitalized cancer patients, as well as literacy and utilization of appropriate professional care. METHODS: All cancer patients (aged 20 to 80 years) who were hospitalized in a university hospital in Tokyo during the designated 3-day period between September 1 and October 31, 2007 were recruited for participation in the study. The M.D. Anderson Symptom Inventory, Brief Cancer-Related Worry Inventory, and Hospital Anxiety and Depression Scale were administered. Patients' knowledge and use of relevant services were evaluated. The results were compared with those of non-cancer patients in the same treatment settings. RESULTS: A total of 125 cancer patients and 59 non-cancer patients were enrolled. Cancer patients and non-cancer patients equally suffered from physical symptoms (15-26% had severe appetite loss, 18-19% had severe dry mouth, and 16-22% had severe pain); however, psychological distress of cancer patients exceeded that of non-cancer patients (28.0% vs 8.5%; p ≤ 0.05). Severe psychological distress was associated with severe worry about future prospects or interpersonal and social issues and presence of two or more severe symptoms. Two thirds of the patients with severe psychological distress knew about the psychiatric division, but only one third actually sought treatment. CONCLUSIONS: Needs related to psychological issues were more prevalent among cancer patients than among non-cancer patients, despite a similar level of physical distress. Special attention should be paid to cancer patients who worry over future prospects or interpersonal and social issues, and those who have two or more severe symptoms.

Differential contributions of prefrontal and hippocampal dopamine D(1) and D(2) receptors in human cognitive functions.

Dopamine D(1) receptors in the prefrontal cortex (PFC) are important for prefrontal functions, and it is suggested that stimulation of prefrontal D(1) receptors induces an inverted U-shaped response, such that too little or too much D(1) receptor stimulation impairs prefrontal functions. Less is known of the role of D(2) receptors in cognition, but previous studies showed that D(2) receptors in the hippocampus (HPC) might play some roles via HPC-PFC interactions. We measured both D(1) and D(2) receptors in PFC and HPC using positron emission tomography in healthy subjects, with the aim of elucidating how regional D(1) and D(2) receptors are differentially involved in frontal lobe functions and memory. We found an inverted U-shaped relation between prefrontal D(1) receptor binding and Wisconsin Card Sorting Test performance. However, prefrontal D(2) binding has no relation with any neuropsychological measures. Hippocampal D(2) receptor binding showed positive linear correlations not only with memory function but also with frontal lobe functions, but hippocampal D(1) receptor binding had no association with any memory and prefrontal functions. Hippocampal D(2) receptors seem to contribute to local hippocampal functions (long-term memory) and to modulation of brain functions outside HPC ("frontal lobe functions"), which are mainly subserved by PFC, via the HPC-PFC pathway. Our findings suggest that orchestration of prefrontal D(1) receptors and hippocampal D(2) receptors might be necessary for human executive function including working memory.

Regional dopamine synthesis in patients with schizophrenia using L-[beta-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.

Case report: Adult phenotype of Mulvihill-Smith syndrome.

Mulvihill-Smith syndrome (MSS) is characterized by premature aging, multiple pigmented nevi, decreased facial subcutaneous fat, microcephaly, short stature, mental retardation and recurrent infections, however the adult phenotype of MSS has yet to be delineated. We report a 28-year-old woman with Mulvihill-Smith syndrome, who had a solid pseudopapillary cystic tumor of her pancreas at age 17 years. Her distinctive sleep pattern includes severe insomnia with disappearance of sleep spindles and K-complexes, persisting muscle tone, and loss of slow wave sleep. The clinical and neurophysiological studies are compatible with agrypnia excitata, a sleep disorder attributable to a dysfunction of the thalamo-limbic system. Brain magnetic resonance imaging and single photon emission computed tomography revealed structural and functional deficits in the dorsomedial region of the thalamus and indicated that an alteration in the thalamo-limbic system may underlie the sleep disturbances in MSS. Furthermore, the rapid and severe decline in acquired cognitive function showed the distinct cognitive impairments resembling dementia, including intellectual deficits, memory disorder and executive dysfunction. We posit that an early onset tumor, sleep disorder and cognitive decline are adult manifestations of Mulvihill-Smith syndrome.

Cognitive neuropsychological and regional cerebral blood flow study of a Japanese-English bilingual girl with specific language impairment (SLI).

We report here on an investigation into the possible factors which might have contributed to language impairment (LI) in EM, a 14-year-old Japanese-English bilingual girl. EM was born in the UK to Japanese parents with no other siblings, and used English to communicate with all other people except for her parents. A delay in her English language development was identified at primary school in the UK, which was attributed to her bilingualism. The deficiency in her English language skills persisted into her adolescence despite more than adequate educational opportunities (including additional language support). At the start of her secondary education, language ability/literacy attainment tests were conducted in both English and Japanese, and the results suggested specific language impairment (SLI) in both languages. Further, her brain Single Photon Emission Computed Tomography (SPECT) revealed significantly lower Regional Cerebral Blood Flow(rCBF) in the left temporo-parietal area, which is also similar to the area of dysfunction often found among Japanese individuals with SLI.

Neural correlates of human virtue judgment.

Neuroimaging studies have demonstrated that the brain regions implicated in moral cognition. However, those studies have focused exclusively on violation of social norms and negative moral emotions, and very little effort has been expended on the investigation of positive reactions to moral excellence. It remains unclear whether the brain regions implicated in moral cognition have specific roles in processing moral violation or, more generally, process human morality per se. Using functional magnetic resonance imaging, brain activations during evaluation of moral beauty and depravity were investigated. Praiseworthiness for moral beauty was associated with activation in the orbitofrontal cortex, whereas blameworthiness for moral depravity was related to the posterior superior temporal sulcus. Humans might have developed different neurocognitive systems for evaluating blameworthiness and praiseworthiness. The central process of moral beauty evaluation might be related to that of aesthetic evaluation. Our finding might contribute to a better understanding of human morality.