Motor Progression and Nigrostriatal Neurodegeneration in Parkinson Disease.

OBJECTIVE: The motor severity in Parkinson disease (PD) is believed to parallel dopaminergic terminal degeneration in the striatum, although the terminal was reported to be virtually absent by 4 years postdiagnosis. Meanwhile, neuromelanin-laden dopamine neuron loss in the substantia nigra (SN) elucidated a variability at early stages and gradual loss with less variability 10 years postdiagnosis. Here, we aimed to clarify the correlation between motor impairments and striatal dopaminergic terminal degeneration and nigral neuromelanin-laden dopamine neuron loss at early to advanced stages of PD. METHODS: Ninety-three PD patients were divided into early and advanced subgroups based on motor symptom duration and whether motor fluctuation was present. Striatal dopaminergic terminal degeneration was evaluated using a presynaptic dopamine transporter tracer, 123 I-ioflupane single photon emission computed tomography (SPECT). Nigral neuromelanin-laden dopamine neuron density was assessed by neuromelanin-sensitive magnetic resonance imaging (NM-MRI). RESULTS: In patients with early stage PD (motor symptoms for ≤8 or 10 years), motor dysfunction during the drug-off state was paralleled by a decline in 123 I-ioflupane uptake in the striatum despite the absence of a correlation with reductions in NM-MRI signals in SN. Meanwhile, in patients with advanced stage PD (motor symptoms for >8 or 10 years and with fluctuation), the degree of motor deficits during the drug-off state was not correlated with 123 I-ioflupane uptake in the striatum, despite its significant negative correlation with NM-MRI signals in SN. INTERPRETATION: We propose striatal dopaminergic terminal loss measured using 123 I-ioflupane SPECT and nigral dopamine neuron loss assessed with NM-MRI as early stage and advanced stage motor impairment biomarkers, respectively. ANN NEUROL 2022;92:110-121.

Subcutaneous fat necrosis after selective head cooling in an infant.

Hypoxic-ischemic encephalopathy in neonates causes irreversible damage to tissue and organs and results in multiple organ failure and poor outcome. Therapeutic hypothermia is the most effective therapy in neonates with hypoxic-ischemic encephalopathy. We report here a case of subcutaneous fat necrosis (SCFN) after therapeutic hypothermia by selective head cooling. Selective head cooling was provided for 72 h after birth. SCFN developed on the patient's cheeks and back at the age of 21 days. Thus, SCFN may be caused by selective head cooling, similarly to whole-body cooling.

Adverse reactions to zolpidem: case reports and a review of the literature.

OBJECTIVE: Zolpidem, a nonbenzodiazepine hypnotic, is very effective and widely prescribed in clinical practice for the treatment of insomnia and is thought to have few adverse effects. However, zolpidem-induced adverse effects have begun to be reported in the literature, but few systemic descriptions of the adverse effects (especially for psychotic reactions) of zolpidem have been undertaken. In light of the accumulating reports of adverse reactions to zolpidem, we present 2 case reports of zolpidem-induced adverse effects and review the literature on this subject. DATA SOURCES: Articles were selected by the authors on the basis of our experience and by a PubMed search using the terms zolpidem or side effects or adverse effects or adverse reactions. STUDY SELECTION AND DATA EXTRACTION: Publications relevant to the objective of this article were obtained (1992-2010), and some adverse neuropsychiatric reactions were summarized. DATA SYNTHESIS: Zolpidem has been associated with the development of adverse neuropsychiatric reactions, such as hallucinations/sensory distortion, amnesia, sleepwalking/somnambulism, and nocturnal eating. The following 4 variables should be considered when prescribing zolpidem: (1) gender: women have been found to have a significantly higher serum zolpidem concentration than men; (2) zolpidem dose: the adverse reactions that develop are dose dependent; (3) protein binding affinity: a high proportion of zolpidem is protein bound; therefore, low serum albumin results in a higher level of free zolpidem leading to adverse psychiatric reactions; and (4) cytochrome P450 (CYP) isoenzyme inhibition: concomitant administration of zolpidem and other drugs may cause interactions that lead to increased concentrations of zolpidem. CONCLUSIONS: Zolpidem is clinically very effective in treating insomnia. However, while rare, zolpidem-induced unusual complex behavior may develop. Primary care physicians should be alert to the possible unusual complex adverse effects of zolpidem.

Abnormalities in MRI signal intensity in schizophrenia associated with idiopathic unconjugated hyperbilirubinemia.

OBJECTIVE: The purpose of the present study was to examine whether patients with idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome; GS) have specific changes in signal intensity on magnetic resonance imaging (MRI). METHODS: Axial 5 mm-thick T1-weighted and T2-weighted MRI was acquired from schizophrenia patients with GS (n = 24) and schizophrenia patients without GS (n = 60). All patients were diagnosed according to DSM-IV criteria and were compared with age- and sex-matched healthy controls without GS (n=60) and controls with GS (n=36). Signal intensity in the hippocampus, amygdala, caudate, putamen, globus pallidus, thalamus, anterior cingulate gyrus, posterior cingulate gyrus, insular cortex, and cerebellum was measured in relation to the signal intensities of the vitreous body. RESULTS: Compared to both schizophrenia patients without GS and the control subjects without or with GS, the schizophrenia patients with GS had significantly decreased signal intensity in almost all the regions measured on T1-weighted MRI. On T2-weighted MRI, the schizophrenia patients with GS had significantly increased signal intensity in almost all the regions measured compared to both schizophrenia patients without GS and the control subjects without or with GS. CONCLUSION: Patients with schizophrenia-associated GS have specific changes in signal intensity on T1- and T2-weighted MRI, suggesting that schizophrenia with GS produces changes specifically in the frontotemporal cortex, limbic system, and basal ganglia.

Yi-gan san as adjunctive therapy for treatment-resistant schizophrenia: an open-label study.

BACKGROUND: Recent studies indicate that the traditional Japanese herbal medicine yi-gan san (YGS; yokukan-san in Japanese) may be safe and useful in treating behavioral and psychological symptoms in patients with dementia and borderline personality disorder. We aimed at evaluating both the efficacy and safety of YGS in patients with treatment-resistant schizophrenia. METHODS: Thirty-four patients diagnosed with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (YGS-free) group (n = 25) and treated in a 4-week open-label study with YGS at an average daily dosage of 6.7 +/- 2.5 g (range, 2.5-7.5 g). Psychometric instruments used to assess efficacy included the Positive and Negative Syndrome Scale for Schizophrenia and the Drug-Induced Extrapyramidal Symptom Scale. RESULTS: A significant decrease was observed at 2 weeks and at 4 weeks in each Positive and Negative Syndrome Scale for Schizophrenia subscale score in the YGS group, but this was not observed in the control group. However, the Drug-Induced Extrapyramidal Symptom Scale total score did not change in both groups. CONCLUSIONS: In this open-label pilot study, patients treated with YGS showed a statistically significant reduction on clinician-rated scales. The present findings suggest that an adjunction of YGS might be effective for treatment-resistant schizophrenia.

New approaches to antidepressant drug design: cytokine-regulated pathways.

Monoamine oxidase inhibitor and tricyclic antidepressants have been serendipitously used for the treatment of depression for more than half a century and subsequently found to promote monoaminergic signals in the brain. Antidepressant drugs are still clinically used and industrially designed on the basis of the monoaminergic theory. Recent developments regarding selective monoaminergic uptake inhibitors can further improve the safe and rational treatment for patients with depression. However, monoamine-based antidepressants may cause unfavorable and incomplete remission of a considerable number of patients with depression; therefore, development of new antidepressant drugs based on other mechanisms is required. Meanwhile, there has been an impressive accumulation of knowledge about cytokines that might contribute to the understanding of the pathophysiology of depression. Therefore, this review focuses on the association between depressive disorder and cytokines and discusses the strategies for developing new cytokine-based antidepressant drugs.

Hyperbilirubinemia-related behavioral and neuropathological changes in rats: a possible schizophrenia animal model.

BACKGROUND: Patients with schizophrenia show a significantly higher frequency of hyperbilirubinemia than patients suffering from other psychiatric disorders and the general healthy population. We examined the hyperbilirubinemia on behavioral and neuropathological changes in rats as a possible animal model of schizophrenia. METHODS: Gunn rats with severe hyperbilirubinemia (j/j), Gunn rats without severe hyperbilirubinemia (+/j), and Wistar rats were examined by open-field, social interaction, and prepulse inhibition tests. TUNEL, AgNOR and Ki-67 were also assayed on paraffin-embedded brain sections of these rats. RESULTS: Compared to Wistar rats, both Gunn j/j and +/j rats showed hyperlocomotion, high sniffing scores, and low defecation scores. They showed significantly more aggressive behaviors and impaired prepulse inhibition. The numbers of Ki-67-labeled cells and AgNOR were lower and the number of TUNEL-positive cells was higher than that of Wistar rats. CONCLUSIONS: These results might support the neurodevelopmental hypothesis of schizophrenia. Both Gunn j/j and +/j rats may be a useful animal model and provide clues to the role of hyperbilirubinemia in schizophrenia.

Temporal alterations in concentrations of sera cytokines/chemokines in sepsis due to group B streptococcus infection in a neonate.

Group B streptococcus (GBS) is the most common pathogen in neonates and may induce the overproduction of cytokines. To further clarify temporal alterations in the levels of various cytokines/chemokines, we measured the concentrations of 16 types of these immunological responders in the serum of a neonate presenting with GBS infection. At birth, the concentrations of different cytokines/chemokines increased and that of granulocyte colony-stimulating factor remained high. Thus, these cytokines/chemokines might be associated with the pathophysiology of GBS infection.

Prediction of response within the first 3 days to treatment with paroxetine for depression.

OBJECTIVE: In the treatment of depression, clinical and psychopharmacologic aspects have been investigated to predict the response to anti-depressants. Some trials have reported clinical improvement as early as the first week; however, few have investigated the early effects of selective serotonin reuptake inhibitors. The aim of this study was to investigate therapeutic efficacy of paroxetine within the first 3 days of therapy onset. METHOD: Subjects included 29 outpatients diagnosed at first interview with major depressive disorder according to DSM-IV criteria (June 2003 to January 2007). Paroxetine 5-20 mg/day was administered for at least 2 weeks. Treatment efficacy was defined as a > 50% decrease in Hamilton Rating Scale for Depression (HAM-D) total scores from baseline to the end of the second week. To determine efficacy within the first 3 days, patients completed the HAM-D as a self-rated questionnaire on the first and third days and at the end of the first, second, and fourth weeks. RESULT: Subjects were divided into 2 groups: successful (17 responders) and failed (12 non-responders). There was a significant difference between the reduction rates of self-rated HAM-D total scores on the third day (p < .01). CONCLUSION: In patients responding to paroxetine in the early stages of treatment, the prediction of response within the first 3 days using the self-rated HAM-D is suggested.

Characterization of the vulnerability to repeated stress in Fischer 344 rats: possible involvement of microRNA-mediated down-regulation of the glucocorticoid receptor.

In the present study, we established and characterized an animal model of vulnerability to repeated stress. We found that control Sprague-Dawley (SD) rats showed a gradual decrease in the HPA axis response following 14 days of repeated restraint stress, whereas Fischer 344 (F344) rats did not show such HPA axis habituation. Similar habituation was observed in the expression of c-fos mRNA, corticotropin-releasing hormone hnRNA, and phospho-CREB and phospho-ERK proteins in the hypothalamic paraventricular nucleus (PVN) of SD rats, but not in the F344 rats. In addition, repeatedly restrained F344 rats exhibited decreased cell proliferation in the dentate gyrus of the hippocampus and increased anxiety-related behaviours, while repeatedly restrained SD rats exhibited a selective enhancement of hippocampal cell proliferation in the ventral area. Moreover, we found a lower expression of glucocorticoid receptor (GR) protein, but not mRNA, in the PVN of F344 rats compared to SD rats. We also identified that microRNA (miR)-18a inhibited translation of GR mRNA in cultured neuronal cells and that increased expression of miR-18a in the PVN was observed in F344 rats compared with SD rats. These strain differences in GR protein levels were not found in the hippocampus and prefrontal cortex, and the expression of miR-18a was much lower in these brain regions than in the PVN. Our results suggest that F344 rats could be a useful animal model for studying vulnerability to repeated stress, and that miR-18a-mediated down-regulation of GR translation may be an important factor to be considered in susceptibility to stress-related disorders.

State-dependent changes in the expression levels of NCAM-140 and L1 in the peripheral blood cells of bipolar disorders, but not in the major depressive disorders.

Recent postmortem brain and imaging studies provide evidence for disturbances of structural and synaptic plasticity in patients with mood disorders. Several lines of evidence suggest that the cell adhesion molecules (CAMs), neural cell adhesion molecules (NCAM) and L1, play important roles in both structural and synaptic plasticity. Although postmortem brain studies have indicated altered expression levels of NCAM and L1, it is still unclear whether these changes are state- or trait-dependent. In this study, the mRNA levels for various CAMs, including NCAM and L1, were measured using quantitative real-time PCR in peripheral blood cells of major depressive disorder patients, bipolar disorder patients and normal healthy subjects. Reduced expression levels of NCAM-140 mRNA were observed in bipolar disorder patients in a current depressive state. In contrast, L1 mRNA levels were increased in bipolar disorder patients in a current depressive state. NCAM-140 and L1 mRNA levels were not changed in bipolar disorder patients in a remissive state, or in major depressive disorder patients. In addition, there were no significant changes in the expression levels of intercellular adhesion molecule -1, vascular cell adhesion molecule -1, E-cadherin, or integrin alphaD among healthy controls, major depressive or bipolar disorder patients. Our results suggest that the reciprocal alteration in the expression of NCAM-140 and L1 mRNAs could be state-dependent and associated with the pathophysiology of bipolar disorder.

Serum cytokine and chemokine profiles in neonates with meconium aspiration syndrome.

OBJECTIVES: Various inflammatory cytokines and chemokines are thought to be associated with the pathophysiology of meconium aspiration syndrome. To clarify any such association, we compared various serum cytokine and chemokine profiles in patients with and without meconium aspiration syndrome. PATIENTS AND METHODS: Using a highly sensitive fluorescence microsphere method, 17 types of cytokines and chemokines in sera were measured in 11 neonatal patients with meconium aspiration syndrome, 16 neonatal patients without meconium aspiration syndrome, and 9 healthy children. RESULTS: The concentrations of 8 types of proinflammatory cytokines and chemokines were significantly higher in the meconium aspiration syndrome group than in healthy controls: interleukin-1beta, interleukin-6, interleukin-8, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, interferon-gamma, macrophage inflammatory protein-1beta, and tumor necrosis factor-alpha. Six types of proinflammatory cytokines and chemokines were significantly higher in the meconium aspiration syndrome group than in the nonmeconium aspiration syndrome group: interleukin-6, interleukin-8, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, interferon-gamma, and tumor necrosis factor-alpha. Serum concentrations of interleukin-10 (anti-inflammatory cytokine) in the meconium aspiration syndrome group were higher than those in both the nonmeconium aspiration syndrome group and healthy children group (P = .007 and 0.001, respectively). CONCLUSIONS: Most types of proinflammatory cytokines and chemokines in sera of neonates with meconium aspiration syndrome were higher than those without meconium aspiration syndrome, giving support to the suggestion that elevated levels are associated with the pathogenesis of meconium aspiration syndrome.

Increased expression of splicing factor SRp20 mRNA in bipolar disorder patients.

BACKGROUND: Variations and defects in alternative splicing are well known to be associated with a variety of human diseases and the stress response. We previously reported a decrease in glucocorticoid receptor (GR) alpha, but not GRbeta in mood disorder patients, suggesting an aberrant alternative splicing mechanism. To examine whether altered RNA splicing may underlie the pathophysiology of mood disorder, we evaluated the expression of a variety of SR protein splicing factors, a family of proteins indispensable for proper alternative splicing, in mood disorder patients. METHODS: We used quantitative real-time PCR to measure expressions of SRp20, SRp30c, SC35, SRp40, SRp46, SRp54, SRp55, SRp75, ASF/SF2, and 9G8 mRNA in peripheral white blood cells of 33 mood disorder patients during a depressive episode. In addition, the expressions of SRp20 and SC35 mRNA were quantified for 78 mood disorder patients in a remissive state, and 32 the first-degree relatives of these mood disorder patients. RESULT: A significant correlation was observed between SRp30c and the GRbeta/GRalpha ratio in control subjects, but not in mood disorder patients. Increased expression of SRp20 but not SRp30c mRNA was observed in bipolar disorder patients in both the depressive and remissive states. Major depressive disorder patients did not show any significant change in mRNA levels of SR proteins. LIMITATION: Subjects were Japanese adults. Patient treatment was not standardized. CONCLUSIONS: These results suggest that aberrant alternative splicing machinery caused by increased SRp20 mRNA expression would be associated with the pathophysiology of bipolar disorder.

Elevation of high-mobility group box 1 concentration in asphyxiated neonates.

BACKGROUND: In asphyxiated neonates, abnormal proinflammatory cytokine/chemokine production may be induced. High-mobility group box 1 (HMGB-1) protein is a new type of proinflammatory cytokine that induces abnormal inflammatory responses involving proinflammatory cytokine production. However, the physiological significance of HMGB-1 in asphyxia is poorly understood. OBJECTIVES: We aimed to evaluate whether serum HMGB-1 levels were changed in asphyxia by measuring the serum concentration of HMGB-1 in both asphyxiated and normally delivered neonates at birth. METHODS: Using enzyme-linked immunosorbent assay, we measured the concentration of HMGB-1 in sera obtained from 53 asphyxiated neonates and 32 normally delivered neonates immediately after birth. RESULTS: The serum concentrations of HMGB-1 in asphyxiated neonates were significantly higher than those in normally delivered neonates without asphyxia (p = 0.033). CONCLUSION: We suggest that the elevation of HMGB-1 might be associated with abnormal inflammatory responses involving the excessive production of proinflammatory cytokines in neonates with asphyxia.

Yi-gan san for the treatment of neuroleptic-induced tardive dyskinesia: an open-label study.

BACKGROUND: Recent studies indicate that the traditional Japanese herbal medicine yi-gan san (YGS, yokukan-san in Japanese), a serotonin modulator, may be safe and useful in treating behavioral and psychological symptoms in dementia and borderline personality disorder patients. The authors examined the efficacy, tolerability, and safety of YGS in patients with tardive dyskinesia. METHODS: Twenty-two patients with schizophrenia who had neuroleptic-induced tardive dyskinesia were given 7.5 g/day of YGS for 12 weeks in an open-label study. RESULTS: Administration of YGS resulted in a statistically significant improvement in tardive dyskinesia and psychotic symptoms. CONCLUSIONS: YGS may be an effective and safe therapy to control tardive dyskinesia and psychosis in patients with schizophrenia, that should be further tested in double-blind, placebo-controlled trials.

Decreased levels of whole blood glial cell line-derived neurotrophic factor (GDNF) in remitted patients with mood disorders.

Recent post-mortem and imaging studies provide evidence for a glial reduction in different brain areas in mood disorders. This study was aimed to test whether glial cell line-derived neurotrophic factor (GDNF), a member of transforming growth factor (TGF)-beta superfamily, in blood levels was associated with mood disorders. We measured GDNF and TGF-beta levels in whole blood in remitted patients with mood disorders [n=56; major depressive disorders (MDD) 39, bipolar disorders (BD) 17] and control subjects (n=56). GDNF and TGF-beta were assayed with the sandwich ELISA method. Total GDNF levels were significantly lower in MDD and in BD than in control subjects (MDD, p=0.0003; BD, p=0.018), while no significant difference in total TGF-beta1 or total TGF-beta2 levels was found in these groups. Our study suggests that lower GDNF levels might be involved in the pathophysiology of mood disorders, although this preliminary study has several limitations.

Elevation of cytokine concentrations in asphyxiated neonates.

BACKGROUND: Various cytokines are reportedly associated with many neonatal diseases. Asphyxia is considered to result in ischemia-reperfusion injuries and induces abnormal inflammatory responses involving excessive cytokine production. OBJECTIVES: To evaluate alteration in sera levels of various cytokines/chemokines in case of perinatal asphyxia at birth. METHODS: In order to determine the concentrations of various cytokines/chemokines in sera, we used a highly sensitive fluorescence microsphere method. We measured the concentration of 8 types of cytokines/chemokines in sera obtained from 17 cases of asphyxia, 10 normal neonates, and 6 healthy adults. RESULTS: The concentrations of IL-6, IL-8, and IL-10 in the sera of asphyxiated neonates were higher than those in the normal neonates. Irrespective of the presence or absence of asphyxia, sera concentrations of IL-2, IL-4, IFN-gamma, and TNF-alpha were higher in the neonates than those in the adults. The concentration of IFN-gamma in the asphyxiated neonates was lower than that in the normal neonates. Sera levels of IL-10 were higher in the asphyxiated cases than those in the normal neonates. The sera levels of IL-6, IL-8, and IL-10 in asphyxiated neonates with either a poor outcome or death were higher than those without poor outcomes. CONCLUSIONS: The concentrations of various types of cytokines/chemokines were different in neonatal sera and some of them increased drastically during asphyxia. The concentration of an anti-inflammatory cytokine IL-10 was elevated in asphyxiated neonates immediately after birth, thereby suggesting that IL-10 might be associated with neuroprotective functions.

[Mechanisms of antidepressants and serotonin (5-HT)-induced glial cell line-derived neurotrophic factor (GDNF) releases in rat C6 gliobrastoma cells].

Recent studies show that neuronal and glial plasticity are important for the therapeutic action of antidepressants. Here, we demonstrated that amitriptyline, a tricyclic antidepressant, significantly increased GDNF mRNA and GDNF release in C6 cells. Furthermore, different classes of antidepressants increased GDNF release, but non-antidepressant psychotropic drugs did not. The amitriptyline-induced GDNF release was completely inhibited by U0126, a mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor, but was not inhibited by H-89, a protein kinase A inhibitor or calphostin C, a protein kinase C inhibitor. These results suggest that the amitriptyline-induced GDNF release may be regulated through a MEK/MAPK pathway. Next, we examined the effects of monoamines on GDNF release, because antidepressants are known to increase monoamines. 5-HT increased GDNF mRNA and GDNF release, but noradrenaline and dopamine did not. The 5-HT-induced GDNF release was partially, but significantly, blocked by ketanserin, a 5-HT2A receptor antagonist. The 5-HT-induced GDNF release was completely inhibited by U0126, but was not inhibited by H-89 or calphostin C. These results suggest that the 5-HT-induced GDNF release was mediated through a MEK/MAPK pathway and, at least, 5-HT2A receptors. GDNF, as well as other neurotrophic factors, may contribute to explain the therapeutic action of antidepressants and suggest a novel strategy of pharmacological intervention.

Pachygyria in a girl with microcephalic osteodysplastic primordial short stature type II.

We report a mild form of lissencephaly or a pachygyric brain in a girl with microcephalic osteodysplastic primordial 'dwarfism' (MOPD) type II. She was born with severe intrauterine growth failure. A diagnosis of MOPD type II was warranted by persistent postnatal growth failure, microcephaly with a Seckel-like facial appearance, and distinctive radiological findings, including overtubulation of the long bones, metaphyseal cupping of the distal femora, and brachyphalangy with ivory epiphyses. Brain MRI showed thickened cerebral cortices with few and large gyri, most prominently in the frontal and posterior temporal regions. The Sylvian fissures developed incompletely, and the posterior horns of the lateral ventricle were dilated (colpocephaly). Despite the severe imaging findings, she showed only mild retardation of psychomotor development. To date, only minor brain malformations have attracted attention in MOPD type II. Our experience may suggest a wider spectrum of brain anomalies in this entity.