Trends in use of psychotropic medications among patients treated with cholinesterase inhibitors in Japan from 2002 to 2010.

BACKGROUND: We aimed to examine trends in the use of psychotropic medications among elderly outpatients with dementia in Japan between 2002 and 2010. METHODS: We used data from the 2002-2010 Survey of Medical Care Activities in Public Health Insurance (SMCA-PHI), a nationally representative cross-sectional survey of claims data for the month of June in every year. We included ambulatory care visits by patients aged 65 years or older who were prescribed cholinesterase inhibitors (n = 15,591), and identified use of any psychotropic medications during the survey month. RESULTS: In 2008­2010, the most prevalently prescribed psychotropic medications to patients with dementia were sedatives-hypnotics (27.3%), antipsychotics (21.3%), antidepressants (11.4%), and mood-stabilizers(2.8%). Between 2002­2004 and 2008­2010, use of second-generation antipsychotics increased from 4.9%to 11.2%, while use of first-generation antipsychotics decreased from 17.4% to 12.1% [corrected].These numbers resulted in a 1.1-fold increase in the adjusted prevalence of the overall use of antipsychotics. Quetiapine and risperidone use showed a 4.8- and 1.8-fold increase, respectively, while haloperidol use showed a 2.3-fold decrease. CONCLUSIONS: Despite safety warnings against the use of antipsychotics for patients with dementia in several countries, our study revealed a slight increase in the extensive use of off-label antipsychotics over time in Japan. This finding indicates an urgent need for evaluation of the efficacy of antipsychotics for the approved treatment of severe agitation, aggression, and psychosis associated with dementia. Moreover, psychosocial interventions and antipsychotic withdrawal strategies are needed in order to reduce the overall prevalence of antipsychotic use.

Autopsy case of concurrent Huntington's disease and neurofibromatosis type 1.

We report here an autopsy case of concurrent Huntington's disease (HD) and neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease. The patient was a Japanese woman with a significant hereditary burden: seven of her family members within four generations were affected by either NF1 or concurrent HD and NF1. She was diagnosed as having NF1 at age 24. At age 40, she showed signs of irritability, aggressive and childish behaviour, which became progressively worse. At age 48, rigidity and spastic gait were observed. One year later, choreoathetoid involuntary movements became apparent. Diagnosis of HD was made by identification of the abnormally expanded cytosine-adenine-guanine repeats in the Huntington's disease gene. Her condition deteriorated gradually to an apallic state and she died at age 60. Post-mortem examination revealed extensive brain atrophy, which was particularly severe in the frontal and temporal cortices and the striatum. The degree of neurodegenerative change seemed to correspond to grade IV. Polyglutamine positive inclusions were seen frequently in all layers of the cerebral cortex and in the amygdala and hippocampus. Inclusions were also present in the striatum, but there were fewer than in the cortex. Remarkably, neuronal intranuclear inclusions were present in the cerebellum, although they are usually not seen in HD. Features associated with the central nervous system involvement of NF1 were not found in the brain, but HD pathology might have been accelerated by the concurrence of NF1. This is the third report of a case with concurrent HD and NF1 in the world, and the first study in which occurrence of polyglutamine inclusions was confirmed on post-mortem examination.

Localization of fused in sarcoma (FUS) protein to the post-synaptic density in the brain.

Mutations in the fused in sarcoma (FUS) gene are linked to a form of familial amyotrophic lateral sclerosis (ALS), ALS6. The FUS protein is a major component of the ubiquitin-positive neuronal cytoplasmic inclusions in both ALS6 and some rare forms of frontotemporal lobar degeneration (FTLD). The latter are now collectively referred to as FTLD-FUS. In the present study, we investigated the localization of FUS in human and mouse brains. FUS was detected by western blot as an approximately 72 kDa protein in both human and mouse brains. Immunohistochemistry using lightly fixed tissue sections of human and mouse brains revealed FUS-positive granular staining in the neuropil, in addition to nuclear staining. Such granules are abundant in the gray matter of the brainstem and spinal cord. They are not frequent in the telencephalon. At the light microscopic level, FUS-positive granules are often co-localized with synaptophysin and present in association with microtubule-associated protein 2-positive dendrites. In the synaptosomal fraction of mouse brain, FUS is detected mainly in the post-synaptic density fraction. Thus, while FUS is primarily a nuclear protein, it may also play a role in dendrites. In the brains of patients with FTLD with TDP-43 deposition (FTLD-TDP), the number of FUS-positive granules in the cortex is increased compared with control cases. The increase in Alzheimer's disease (AD) is less remarkable but still significant. The dendritic localization of FUS and its increase in FTLD-TDP and AD may have some implication for the pathophysiology of neurodegenerative diseases.

Progressive nonfluent aphasia: a rare clinical subtype of FTLD-TDP in Japan.

Progressive nonfluent aphasia (PNFA) is a clinical subtype of frontotemporal lobar degeneration (FTLD). FTLD with tau accumulation (FTLD-tau) and FTLD with TDP-43 accumulation (FTLD-TDP) both cause PNFA. We reviewed clinical records of 29 FTLD-TDP cases in the brain archive of our institute and found only one case of PNFA. The patient was an 81-year-old male at death. There was no family history of dementia or aphasia. He presented with slow, labored and nonfluent speech at age 75. Behavioral abnormality and movement disorders were absent. MRI at age 76 demonstrated atrophy of the perisylvian regions, including the inferior frontal gyrus, insular gyrus and superior temporal gyrus. The atrophy was more severe in the left hemisphere than the right. On post mortem examinations, neuronal loss was evident in these regions as well as in the substantia nigra. There were abundant TDP-43-immunoreactive neuronal cytoplasmic inclusions and round or irregular-shaped structures in the affected cerebral cortices. A few dystrophic neurites and neuronal intranuclear inclusions were also seen. FTLD-TDP showing PNFA seems to be rare but does exist in Japan, similar to that in other countries.

Gray matter lesions in Nasu-Hakola disease: a report on three autopsy cases.

Nasu-Hakola disease is an autosomal recessively inherited disease characterized by lipomembranous polycystic osteodysplasia and sclerosing leukoencephalopathy. While white matter lesions prominent in the brain have been reported in the literature, gray matter lesions have not received particular attention. In this study, we examined three autopsy cases of Nasu-Hakola disease in order to focus specifically on gray matter lesions. The ages at onset of the three cases were 20, 23 and 29 years, and the disease durations were 29, 19 and 8 years, respectively. In addition to characteristic degeneration in the cerebral white matter, such as demyelination with conspicuous fibrillary gliosis and axonal changes, all three cases showed overt pathology in the gray matter. Neuronal loss with gliosis in the thalamus (particularly in the dorsomedial nucleus and anterior nucleus), caudate nucleus, putamen and substantia nigra was prominent in all cases, and the severity corresponded to the disease duration. The cerebral cortices were relatively preserved in all cases. One case showed neuronal loss and gliosis in the gray matter of the hippocampus, possibly due to repeated episodes of epileptic convulsions. These gray matter pathologies are considered to be responsible for some of the clinical manifestations of the disease, including extrapyramidal symptoms.

GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation.

GIGYF2 has been reported as a candidate gene for PARK11-linked Parkinson's disease (PD). Heterozygous knockout of GIGYF2 results in neurodegeneration, suggesting important roles for GIGYF2 (Grb10 interacting GYF protein 2) in the CNS. In this study, we used novel GIGYF2 antibodies to clarify the distribution and function of GIGYF2. GIGYF2 was widely expressed, most highly in the pancreas and testis, and moderately in brain, lung, liver, kidney and spleen. In the brain, GIGYF2 was tightly associated with membrane in the S3 fraction, and localised in neuronal perikarya and proximal dendrites. Immunohistochemical analysis indicated sites of GIGYF2 localisation throughout the mouse brain, with high levels in the cerebral cortex, hippocampus, cerebellum, olfactory bulb and brainstem nuclei, but low levels in the substantia nigra and striatum. GIGYF2 was present in endosomes immunopositive for Rab4 and Grb10. Expression of GIGYF2 altered insulin-like growth factor-1 (IGF-1) receptor trafficking and enhanced IGF-1-induced extracellular signal-regulated kinase 1/2 phosphorylation, but not IGF-1 receptor or serine/threonine protein kinase Akt phosphorylation. There were no significant differences in signalling activation between cells expressing wild-type and putative PD-associated mutant GIGYF2. In PD brains, GIGYF2 did not localise to Lewy bodies. Our findings indicate a role for GIGYF2 in the regulation of signalling at endosomes, but no contribution of GIGYF2 to the pathogenesis of PD.

Administration of zonisamide in three cases of dementia with Lewy bodies.

Zonisamide (ZNS) add-on administration was used to treat parkinsonian symptoms in three cases of dementia with Lewy bodies (DLB). ZNS was added after doses of the anti-Parkinson's disease drugs were fixed for at least 4 weeks. A total of 25 mg of ZNS produced mild-moderate improvement of parkinsonian symptoms in two cases, but it did not affect the cognitive functions and behavioral or psychological symptoms. Caregiver burdens were decreased in two cases. Although dizziness and drowsiness were detected, these were improved by decreasing the dose. ZNS may be useful for the treatment of motor symptoms in DLB patients.

Abnormal localization of leucine-rich repeat kinase 2 to the endosomal-lysosomal compartment in lewy body disease.

Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common causes of both familial and sporadic forms of Parkinson disease and are also associated with diverse pathological alterations. The mechanisms whereby LRRK2 mutations cause these pathological phenotypes are unknown. We used immunohistochemistry with 3 distinct anti-LRRK2 antibodies to characterize the expression of LRRK2 in the brains of 21 subjects with various neurodegenerative disorders and 7 controls. The immunoreactivity of LRRK2 was localized in a subset of brainstem-type Lewy bodies (LBs) but not in cortical-type LBs, tau-positive inclusions, or TAR-DNA-binding protein-43-positive inclusions. The immunoreactivity of LRRK2 frequently appeared as enlarged granules or vacuoles within neurons of affected brain regions, including the substantia nigra, amygdala, and entorhinal cortex in patients with Parkinson disease or dementia with LBs. The volumes of LRRK2-positive granular structures in neurons of the entorhinal cortex were significantly increased in dementia with LBs brains compared with age-matched control brains (p < 0.05). Double immunolabeling demonstrated that these LRRK2-positive granular structures frequently colocalized with the late-endosomal marker Rab7B and occasionally with the lysosomal marker, the lysosomal-associated membrane protein 2. These results suggest that LRRK2 normally localizes to the endosomal-lysosomal compartment within morphologically altered neurons in neurodegenerative diseases, particularly in the brains of patients with LB diseases.

Accumulation of phosphorylated TDP-43 in brains of patients with argyrophilic grain disease.

To determine whether TAR-DNA binding protein 43 (TDP-43) immunoreactivity was present in brains of argyrophilic grain disease (AGD), we immunohistochemically examined 15 cases of AGD (mean age at death: 84 years) using a panel of anti-TDP-43 antibodies, including both phosphorylation-independent and -dependent ones. Nine AGD cases (60%) showed TDP-43 immunoreactivities mainly in the limbic regions and lateral occipitotemporal cortex. TDP-43 positive structures included neuronal cytoplasmic inclusions, dystrophic neurites, glial cytoplasmic inclusions, grain-like dot-shaped structures, and neurofibrillary tangle (NFT)-like structures. The distribution of these TDP-43 positive structures was largely consistent with that of argyrophilic grains. Double-labeling confocal microscopy revealed, however, that many of phospho-TDP-43 positive structures were not colocalized with phospho-tau staining. Colocalization of phospho-TDP-43 and phospho-tau was observed only in part of neuronal cytoplasmic inclusions, grain-like structures and NFT-like structures. There were no differences in demographics, disease duration, brain weight, NFT Braak stage, or severity of amyloid burden between AGD cases with and without TDP-43-immunoreactivity. However, cases of AGD with TDP-43-immunoreactivity were assigned to higher AGD stages than those without TDP-43-immunoreactivity (P < 0.05). Furthermore, the TDP-43 pathology tended to be prominent in cases with severe grain pathology. The results of the present study indicate for the first time a high frequency of concomitant TDP-43 pathology in AGD, and suggest that abnormal accumulation of TDP-43 may be involved in the pathological process and disease progression of AGD.

Neuropathological investigation of regions responsible for semantic aphasia in frontotemporal lobar degeneration.

BACKGROUND/AIMS: Semantic dementia is a subtype of frontotemporal lobar degeneration, of which an initial symptom is semantic aphasia. Semantic dementia pathologically corresponds to atypical Pick's disease (aPiD), showing ubiq- uitin-positive inclusions similar to those in dementia with motor neuron disease (D-MND). Previous studies have not clarified the regions responsible for semantic aphasia in aPiD, and there have been no reported neuropathological studies concerning its pathomechanism. METHODS: We neuropathologically investigated aPiD and D-MND cases with and without semantic aphasia. RESULTS: We determined that the regions involved in the early stage of the disease course of semantic dementia were more restricted to the anterior and inferior portion of the temporal lobe on the side of the dominant hemisphere. CONCLUSION: Degeneration of the temporal pole is most likely to participate in the pathomechanism of SA in semantic dementia.

Evaluation of subjective treatment satisfaction with antipsychotics in schizophrenia patients.

Adherence to antipsychotic treatment is particularly important in the long-term management of schizophrenia and other related psychotic disorders since poor adherence to medication is associated with poor health outcomes. Although the patients' subjective satisfaction with the medication is crucial for adherence to medication, few studies have examined the relationship between subjective satisfaction with antipsychotics and adherence. In this study, we investigated subjective satisfaction with antipsychotics in patients with schizophrenia by using the Treatment Satisfaction Questionnaire for Medication (TSQM), a self-reporting instrument to assess the major dimensions of patients' satisfaction with their medication. The subjects included 121 clinically stabilized outpatients who met the following criteria: 1) patients between 20 and 65 years of age, diagnosed with schizophrenia or other psychotic disorders as defined by DSM-IV, 2) patients undergoing oral antipsychotic monotherapy or taking only an antiparkinsonian agent as an adjuvant remedy, and 3) patients who had received a stable dose of an antipsychotic for more than four weeks. Patients were asked to answer the TSQM questions, and their clinical symptoms were also evaluated by the Brief Psychiatric Rating Scale (BPRS). Satisfaction with regard to side-effects (p=0.015) and global satisfaction (p=0.035) were significantly higher in patients taking second-generation antipsychotics (SGAs, n=111) than those taking first-generation antipsychotics (FGAs, n=10), whereas no significant difference was found between the two groups in clinical symptoms according to BPRS (p=0.637) or the Drug-induced Extrapyramidal Symptoms Scale (DIEPSS, p=0.209). In addition, correlations were not significant between the subjective satisfactions and clinician-rated objective measures of the symptoms. These findings suggest that SGAs have more favorable subjective satisfaction profiles than FGAs in the treatment of schizophrenia. Since it is often difficult to detect the difference by a traditional objective assessment of the patients, it is desirable that physicians pay attention to the patients' subjective satisfaction in conjunction with their own objective clinical assessment.

Total Mini-Mental State Examination score and regional cerebral blood flow using Z score imaging and automated ROI analysis software in subjects with memory impairment.

OBJECTIVE: The Mini-Mental State Examination (MMSE) is considered a useful supplementary method to diagnose dementia and evaluate the severity of cognitive disturbance. However, the region of the cerebrum that correlates with the MMSE score is not clear. Recently, a new method was developed to analyze regional cerebral blood flow (rCBF) using a Z score imaging system (eZIS). This system shows changes of rCBF when compared with a normal database. In addition, a three-dimensional stereotaxic region of interest (ROI) template (3DSRT), fully automated ROI analysis software was developed. The objective of this study was to investigate the correlation between rCBF changes and total MMSE score using these new methods. METHODS: The association between total MMSE score and rCBF changes was investigated in 24 patients (mean age +/- SD 71.5 +/- 9.2 years; 6 men and 18 women) with memory impairment using eZIS and 3DSRT. Step-wise multiple regression analysis was used for multivariate analysis, with the total MMSE score as the dependent variable and rCBF change in 24 areas as the independent variable. RESULTS: Total MMSE score was significantly correlated only with the reduction of left hippocampal perfusion but not with right (P < 0.01). CONCLUSIONS: Total MMSE score is an important indicator of left hippocampal function.

Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer's disease and dementia with Lewy bodies.

TAR-DNA-binding protein 43 (TDP-43) has been identified as a major component protein of ubiquitin-positive inclusions in brains from patients with frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. To obtain the precise prevalence of TDP-43 pathology in neurodegenerative disorders, we examined brains from patients with tauopathies and synucleinopathies as well as FTLD-U using immunohistochemical analysis. Consequently, TDP-43-positive inclusions within neurons and oligodendroglia were found in brains from patients with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) in addition to FTLD-U, but not with Parkinson's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration or FTDP-17. The amygdala and hippocampus that were vulnerable to tau or alpha-synuclein pathology demonstrated more severe TDP-43 pathology in AD and DLB cases than in FTLD-U cases. In contrast, in the frontal cortex and basal ganglia that were vulnerable to TDP-43 pathology in FTLD-U, TDP-43 pathology was not observed in AD and DLB cases. Thus, the neuroanatomical distribution of TDP-43 pathology in AD and DLB cases was obviously different from that in FTLD-U cases. Furthermore, a subset of TDP-43-positive inclusions co-existed with neurofibrillary tangles (NFTs) or Lewy bodies (LBs) in the same neurons. Upon double-immunofluorescent labeling analysis, TDP-43 was hardly superimposed with tau, while TDP-43 was partially superimposed with alpha-synuclein, suggesting that neither NFTs nor LBs themselves show TDP-43 immunoreactivity and that TDP-43 pathology found in this study may be related in some way to AD and LB pathology. This study will provide a more in-depth understanding of the various pathogenic pathways leading to neurodegenerative disorders.

Appearance pattern of TDP-43 in Japanese frontotemporal lobar degeneration with ubiquitin-positive inclusions.

TAR-DNA-binding protein 43 (TDP-43) was identified as a major component of ubiquitin-positive intracellular inclusions from brains of patients with frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Here, we immunohistochemically investigated the appearance pattern of TDP-43 to compare the distribution of TDP-43-positive structures with that of ubiquitin-positive structures in brains of seven patients with Japanese FTLD-U, five of atypical Pick's disease (aPiD) and two of dementia with motor neuron disease (D-MND), as well as two patients with PiD as control. TDP-43-immunoreactivity generally colocalized to ubiquitin-immunoreactivity in both neuronal cytoplasmic inclusions and neurites in FTLD-U brains, but TDP-43-immunoreactivity alone or ubiquitin-immunoreactivity alone was also observed. In five aPiD cases, double-immunostaining with TDP-43 and ubiquitin demonstrated that diffuse neuronal cytoplasmic immunostaining for ubiquitin did not always display TDP-43-immunoreactivity. In contrast, ubiquitin-positive neuronal cytoplasmic inclusions usually displayed TDP-43-immunoreactivity in two D-MND cases, although most glial inclusions in one of two cases were immunostained only for TDP-43. TDP-43-positive structures were not detected in two PiD cases. Thus, the ratio in the appearance pattern of TDP-43 and ubiquitin was different between aPiD and D-MND, leading to the hypothesis that this difference may be associated with the two pathogenic variants related to clinical and pathological heterogeneity in FTLD-U.

Correlation in Lewy pathology between the claustrum and visual areas in brains of dementia with Lewy bodies.

We investigated Lewy pathologies in the claustrum and the related cerebral cortices and subcortical nuclei of dementia with Lewy bodies (DLB) brains using alpha-synuclein-immunohistochemistry to clarify the relationship between Lewy pathology in the claustrum and visual misidentification of DLB patients. The claustrum is known to have strong reciprocal connections with the visual areas. Consequently, the claustrum demonstrated many Lewy bodies (LB) and LB-related neurites. The insular and inferior temporal cortices, amygdala, BA 18, 19, transentohrinal and cingulate cortices showed stronger or similar Lewy pathology as compared with the claustrum, while BA 17, precentral, postcentral and transverse temporal cortices showed weaker Lewy pathology. Comparing the correlation coefficient of Lewy pathology between the clausturm and other regions, BA 18 and 19 as well as the insular and transentorhinal cortices demonstrated a higher correlation coefficient. These findings suggest that Lewy pathology in the claustrum is more closely associated with that in visual areas than in auditory, somatosensory or motor areas, and that dysfunction of the visuo-claustral pathway participates in visual misidentification in addition to the visuo-amygdaloid pathway. The paralimbic cortices including the insular and transentorhinal cortices may connect visual areas with limbic areas by relay of the visuo-claustral or visuo-amygdaloid pathway.

Perospirone in treatment of Huntington's disease: a first case report.

Huntington's disease (HD) is a hereditary disorder clinically characterized by involuntary movements, cognitive decline and psychiatric symptoms. We report on a patient with HD, whose involuntary movements and psychiatric symptoms were clinically improved with perospirone, a second-generation antipsychotic agent with antagonistic effects on serotonin 5-HT(2A) and dopamine D(2) (D(2)) receptors, as well as a unique agonistic effect on serotonin 5-HT(1A) (5-HT(1A)) receptors. The fact that perospirone antagonizes D(2) receptors could explain its effects on the hyperkinetic syndrome, while its agonistic effects on 5-HT(1A) receptors may explain the amelioration of psychiatric symptoms (fear and anxiety) in this patient. Future studies would be valuable to elucidate the utility of perospirone for the treatment of involuntary movements and psychiatric symptoms in HD.

Perospirone augmentation of paroxetine in treatment of refractory obsessive-compulsive disorder with depression.

Obsessive-compulsive disorder (OCD) is often complicated by depression. We report on a patient with treatment-refractory OCD and treatment-refractory major depression who demonstrated a robust response to augmentation of paroxetine with perospirone. Perospirone is a second-generation antipsychotic agent with antagonist effects on both serotonin 5-HT(2A) and dopamine D(2) receptors, as well as a unique agonist effects on serotonin 5-HT(1A) receptors. Future studies would be valuable to elucidate the utility of augmentation therapy of selective serotonin reuptake inhibitors with perospirone in the treatment of refractory OCD with depression.

Immunohistochemical investigation of neurofibrillary tangles and their tau isoforms in brains of limbic neurofibrillary tangle dementia.

Limbic neurofibrillary tangle dementia (LNTD) is a subset of senile dementia characterized by numerous neurofibrillary tangles (NFT) in the hippocampal area, although there is an absence or scarcity of amyloid deposits (AM) throughout the brain. In the present study, we immunohistochemically investigated regional numbers and tau isoforms of NFT in the hippocampal area of nine LNTD patients with anti-three-repeat (3R) tau-specific and anti-four-repeat (4R) tau-specific antibodies, differentiating NFT into three developmental stages of pretangles (PT), NFT and ghost tangles (GT). Consequently, most PT were 4R tau-positive, most GT were 3R tau-positive, and NFT were 3R tau-, 4R tau- or double-positive, suggesting that composition of tau isoforms may shift from a 4R tau-predominant pattern to a 3R tau-predominant pattern during the development of NFT. In addition, a large number of NFT showing different developmental stages and different rates of 3R tau- and 4R tau-positive neurons according to the region were found in the hippocampal area, suggesting that regions undergoing earlier NFT formation may show higher ratio of 3R tau-positive neurons to 4R tau-positive neurons, and that NFT formation may begin in the entorhinal and transentorhinal cortices, subsequently progress to the subiculum and CA1, and further to the CA2, amygdala and CA3-4, although progression to the neocortex is limited. Furthermore, 4R tau-positive astrocytes and grains were found in several patients, suggesting that LNTD is a form of tauopathy.

Investigation of Lewy pathology in the visual pathway of brains of dementia with Lewy bodies.

We examined 19 autopsied cases of dementia with Lewy bodies (DLB) using pathological and alpha-synuclein-immunohistochemical methods, and investigated Lewy pathology in the primary visual pathway (lateral geniculate body and Brodmann's area 17), secondary visual pathway (pulvinar, Brodmann's areas 18 and 19, and inferior temporal cortex), amygdala and substantia nigra, to clarify the relationship between visual misidentification and Lewy pathology in the visual pathway. Consequently, the secondary visual pathway revealed significantly severer Lewy pathology than the primary visual pathway, suggesting that the degeneration of the secondary visual pathway induces dysfunction in the recognition of objects shape and color. In addition, the amygdala revealed significantly severer Lewy pathology and neuronal loss than the primary and secondary visual pathways, suggesting that the degeneration of the amygdala, which receives the afferent connections from the substantia nigra, fails to modulate the visual processing according to cognition and emotion. These findings suggest that Lewy pathologies in the secondary visual pathway and amygdala may cause the dysfunction of the visuo-amygdaloid pathway and participate in visual misidentification in DLB patients. In addition, we compared Lewy pathology between cases with and without visual hallucinations, and showed no significant differences between the two groups.

Early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin in patients with schizophrenia.

Although treatment with antipsychotics, particularly olanzapine and clozapine, has been implicated in weight gain and higher incidence of diabetes, the mechanism of these adverse reactions remains unclear. The purposes of this study were to explore the early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin, three recently identified hormones that play crucial roles in the regulation of energy balance and glucose metabolism. Thirteen patients with schizophrenia who had not received any medication in the 4 weeks prior to this study were included. The patients received olanzapine at an average dose of 14.5mg/day. Serum levels of ghrelin, adiponectin, leptin and insulin, as well as weight and fasting glucose, were investigated at the baseline and at 4 weeks. Serum ghrelin levels had decreased (p 0.03) and leptin had increased (p 0.02), while adiponectin and insulin levels had not significantly changed at Week 4 (p 0.29 and p 0.25, respectively). Weight had increased (p 0.01), while fasting glucose had not significantly changed (p 0.46). These findings suggest that ghrelin levels decrease and leptin levels increase after initiation of olanzapine therapy. Weight gain is also considered to be an early change, while change in insulin sensitivity is not an early change of treatment with olanzapine. Further large-scale and longitudinal studies are warranted to elucidate metabolic changes involving ghrelin, adiponectin, leptin and insulin and their impact on weight and glucose metabolism during treatment with olanzapine and other antipsychotics.